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Hassan M, Vinagolu-Baur J, Li V, Frasier K, Herrick G, Scotto T, Rankin E. E-cigarettes and arterial health: A review of the link between vaping and atherosclerosis progression. World J Cardiol 2024; 16:707-719. [PMID: 39734821 PMCID: PMC11669975 DOI: 10.4330/wjc.v16.i12.707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/05/2024] [Accepted: 09/10/2024] [Indexed: 11/26/2024] Open
Abstract
Recent studies have suggested an evolving understanding of the association between vaping, specifically electronic cigarette (e-cigarette) use, and the progression of atherosclerosis, a significant contributor to cardiovascular disease. Despite the prevailing perception of vaping as a safer alternative to traditional tobacco smoking, accumulating evidence suggests that the aerosols emitted by e-cigarettes contain harmful constituents that may promote endothelial dysfunction, oxidative stress, inflammation, and dyslipidemia-key mechanisms implicated in atherosclerosis pathogenesis. While past research, including experimental studies and clinical investigations, has shed light on the potential cardiovascular risks associated with vaping, gaps in knowledge persist. Future research endeavors should focus on interpreting the long-term effects of vaping on atherosclerosis development and progression, exploring the impact of different e-cigarette formulations and user demographics, and identifying effective strategies for mitigating the cardiovascular consequences of vaping. By identifying and addressing these research gaps, we can enhance our understanding of the cardiovascular implications of vaping and inform evidence-based interventions and policies to safeguard public health.
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Affiliation(s)
- Muhammad Hassan
- Department of Medicine, Nuvance Health, Vassar Brothers Medical Center, Poughkeepsie, NY 12601, United States
| | - Julia Vinagolu-Baur
- Department of Medical Education, State University of New York, Upstate Medical University, Syracuse, NY 13210, United States
| | - Vivian Li
- Department of Medicine, Nuvance Health, Vassar Brothers Medical Center, Poughkeepsie, NY 12601, United States.
| | - Kelly Frasier
- Department of Medicine, Nuvance Health, Vassar Brothers Medical Center, Poughkeepsie, NY 12601, United States
| | - Grace Herrick
- Department of Medical Education, Alabama College of Osteopathic Medicine, Dothan, AL 36303, United States
| | - Tiffany Scotto
- Department of Medicine, University of Florida Health, Jacksonville, FL 32209, United States
| | - Erica Rankin
- Department of Medical Education, Nova Southeastern University Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, FL 33328, United States
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Abellán Alemán J, Sabaris RC, Pardo DE, García Donaire JA, Romanos FG, Iriso JI, Penagos LM, Iglesias LJN, de Salinas APM, Pérez-Monteoliva NRR, Lezcano PSR, Saborido MT, Roca FV. Documento de consenso sobre tabaquismo y riesgo vascular. HIPERTENSION Y RIESGO VASCULAR 2024; 41 Suppl 1:S1-S85. [PMID: 38729667 DOI: 10.1016/s1889-1837(24)00075-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
Consensus statement on smoking and vascular risk About 22% of the Spanish population are daily smokers. Men are more likely to smoke than women. In Spain, women between 15-25 years of age smoke as much or more than men. Every smoker should be assessed for: physical dependence on nicotine (Fagerström test), social and psychological dependence (Glover Nilsson test), level of motivation to quit (Richmond test), probability of therapy success (Henri-Mondor and Michael-Fiore tests), and stage of behavioral change development (Prochaska and DiClementi). Advice on smoking cessation is highly cost-effective and should always be provided. Smoking is an enhancer of cardiovascular risk because it acts as a pathogen agent in the development of arteriosclerosis and is associated with ischemic heart disease, stroke, and peripheral artery disease. Smoking increases the risk of chronic lung diseases (COPD) and is related to cancers of the lung, female genitalia, larynx, oropharynx, bladder, mouth, esophagus, liver and biliary tract, and stomach, among others. Combined oral contraceptives should be avoided in women smokers older than 35 years of age due to the risk of thromboembolism. In smoking cessation, the involvement of physicians, nurses, psychologists, etc. is important, and their multidisciplinary collaboration is needed. Effective pharmacological treatments for smoking cessation are available. Combined treatments are recommended when smoker's dependence is high. For individuals who are unable to quit smoking, a strategy based on tobacco damage management with a total switch to smokeless products could be a less dangerous alternative for their health than continuing to smoke.
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Affiliation(s)
- José Abellán Alemán
- Sociedad Murciana de Hipertensión Arterial y Riesgo Cardiovascular, Cátedra de Riesgo Cardiovascular, Universidad Católica de Murcia, Murcia, España.
| | - Rafael Crespo Sabaris
- Sociedad Riojana de Hipertensión y Riesgo Vascular, Centro de Salud de Entrena, La Rioja, España
| | - Daniel Escribano Pardo
- Sociedad Aragonesa de Hipertensión y Riesgo Vascular, Centro de Salud Oliver, Zaragoza, España
| | - José Antonio García Donaire
- Sociedad Española de Hipertensión, Unidad de Hipertensión, Servicio de Medicina Interna, Hospital Clínico Universitario San Carlos, Madrid, España
| | - Fernando García Romanos
- Sociedad de Hipertensión y Riesgo Vascular de las Illes Balears, Centro de Salud Santa Catalina, Palma de Mallorca, España
| | - Jesús Iturralde Iriso
- Sociedad Vasca de Hipertensión y Riesgo Vascular, Centro de Salud la Habana-Cuba, Vitoria-Gasteiz, España
| | - Luis Martín Penagos
- Sociedad Cántabra de Hipertensión y Riesgo Vascular, Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, España
| | - L Javier Nieto Iglesias
- Sociedad Castilla-La Mancha de Hipertensión y Riesgo Vascular, Unidad de Hipertensión y Riesgo Vascular, Servicio de Nefrología, Hospital General Universitario de Ciudad Real, Ciudad Real, España
| | - Alfonso Pobes Martínez de Salinas
- Sociedad Asturiana de Hipertensión y Riesgo Vascular, Área de Gestión Clínica, Interáreas de Nefrología VII y VIII del SESPA, Asturias, España
| | | | - Pablo Sánchez-Rubio Lezcano
- Sociedad Aragonesa de Hipertensión y Riesgo Vascular, Servicio de Medicina Interna, Hospital General Universitario San Jorge, Huesca, España
| | - Maribel Troya Saborido
- Sociedad Catalana de Hipertensión y Riesgo Vascular, Servicio de Nefrología, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, España
| | - Francisco Valls Roca
- Sociedad Valenciana de Hipertensión y Riesgo Vascular, Centro de Salud de Beniganim, Valencia, España
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He Y, Pavanello C, Hutchins PM, Tang C, Pourmousa M, Vaisar T, Song HD, Pastor RW, Remaley AT, Goldberg IJ, Costacou T, Sean Davidson W, Bornfeldt KE, Calabresi L, Segrest JP, Heinecke JW. Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs. Circulation 2024; 149:774-787. [PMID: 38018436 PMCID: PMC10913861 DOI: 10.1161/circulationaha.123.065959] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/05/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. METHODS We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. RESULTS We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometric analysis of chemically cross-linked peptides and molecular dynamics simulations of APOA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs (like reconstituted HDLs) are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. CONCLUSIONS We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of APOA1 are "flipped" off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
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Affiliation(s)
- Yi He
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
| | - Chiara Pavanello
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy (C.P., L.C.)
| | - Patrick M. Hutchins
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
| | - Chongren Tang
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
| | - Mohsen Pourmousa
- Laboratory of Computational Biology, National Heart, Lung, and Blood Institute (M.P., R.W.P.), National Institutes of Health, Bethesda, MD
| | - Tomas Vaisar
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
| | - Hyun D. Song
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (H.D.S., J.P.S.)
| | - Richard W. Pastor
- Laboratory of Computational Biology, National Heart, Lung, and Blood Institute (M.P., R.W.P.), National Institutes of Health, Bethesda, MD
| | - Alan T. Remaley
- Department of Laboratory Medicine (A.T.R.), National Institutes of Health, Bethesda, MD
| | - Ira J. Goldberg
- Department of Medicine, New York University, New York, NY (I.J.G.)
| | - Tina Costacou
- Department of Epidemiology, University of Pittsburgh, PA (T.C.)
| | - W. Sean Davidson
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, OH (W.S.D.)
| | - Karin E. Bornfeldt
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
| | - Laura Calabresi
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Italy (C.P., L.C.)
| | - Jere P. Segrest
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (H.D.S., J.P.S.)
| | - Jay W. Heinecke
- Department of Medicine, University of Washington, Seattle (Y.H., P.M.H., C.T., T.V., K.E.B., J.W.H.)
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He Y, Pavanello C, Hutchins PM, Tang C, Pourmousa M, Vaisar T, Song HD, Pastor RW, Remaley AT, Goldberg IJ, Costacou T, Davidson WS, Bornfeldt KE, Calabresi L, Segrest JP, Heinecke JW. Flipped C-Terminal Ends of APOA1 Promote ABCA1-dependent Cholesterol Efflux by Small HDLs. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.11.03.23297986. [PMID: 37961344 PMCID: PMC10635269 DOI: 10.1101/2023.11.03.23297986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Background Cholesterol efflux capacity (CEC) predicts cardiovascular disease (CVD) independently of HDL cholesterol (HDL-C) levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 pathway, but the underlying mechanisms are unclear. Methods We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)-deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of APOA1 in the different particles, and the CECs of plasma and isolated HDLs. Results We quantified macrophage and ABCA1 CEC of four distinct sizes of reconstituted HDL (r-HDL). CEC increased as particle size decreased. MS/MS analysis of chemically crosslinked peptides and molecular dynamics simulations of APOA1 (HDL's major protein) indicated that the mobility of that protein's C-terminus was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, whose small HDLs-like r-HDLs-are discoidal and composed of APOA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3-5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. Conclusions We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the two antiparallel molecules of APOA1 are flipped off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased CVD risk. Thus, extra-small and small HDLs may be key mediators and indicators of HDL's cardioprotective effects.
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Affiliation(s)
- Yi He
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Chiara Pavanello
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Patrick M Hutchins
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Chongren Tang
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Mohsen Pourmousa
- Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
| | - Tomas Vaisar
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Hyun D Song
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37240, USA
| | - Richard W Pastor
- Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
| | - Alan T Remaley
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD 20892
| | - Ira J Goldberg
- Department of Medicine, New York University, New York, NY, 10016, USA
| | - Tina Costacou
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - W Sean Davidson
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, USA
| | - Karin E Bornfeldt
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
| | - Laura Calabresi
- Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Jere P Segrest
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37240, USA
| | - Jay W Heinecke
- Department of Medicine, University of Washington, Seattle, WA, 98109, USA
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Abeer MI, Abdulhasan A, Haguar Z, Narayanaswami V. Isoform-specific modification of apolipoprotein E by 4-hydroxynonenal: protective role of apolipoprotein E3 against oxidative species. FEBS J 2023; 290:3006-3025. [PMID: 36661393 PMCID: PMC11296219 DOI: 10.1111/febs.16729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/02/2022] [Accepted: 01/18/2023] [Indexed: 01/21/2023]
Abstract
High levels of 4-hydroxynonenal (HNE), arising from lipid peroxidation, and HNE-modified proteins have been identified in postmortem brains of ageing and Alzheimer's disease (AD) patients. The goal of this study is to understand the effect of HNE modification on the structure and function of recombinant apolipoprotein E3 (apoE3) and apolipoprotein E4 (apoE4), which play a critical role in brain cholesterol homeostasis. The two isoforms differ in a single amino acid at position 112: Cys in apoE3 and Arg in apoE4. Immunoblot with HNE-specific antibody indicates HNE modification of apoE3 and apoE4 with a major band at ~ 36 kDa, while LC-MS/MS revealed Michael addition at His140 (60-70% abundance) and His299 (3-5% abundance) in apoE3 and apoE4, and Cys112 adduct in apoE3 (75% abundance). Circular dichroism spectroscopy revealed no major differences in the overall secondary structure or helical content between unmodified and HNE-modified apoE. HNE modification did not affect their ability to promote cholesterol efflux from J774.1 macrophages. However, it led to a 3-fold decrease in their ability to bind lipids and 25-50% decrease in the ability of cerebral cortex endothelial cells to uptake lipoproteins bearing HNE-modified HNE-apoE3 or HNE-apoE4 as noted by fluorescence microscopy and flow cytometry. Taken together, the data indicate that HNE modification impairs lipid binding and cellular uptake of both isoforms, and that apoE3, bearing a Cys, offers a protective role by sequestering lipid peroxidation products that would otherwise cause indiscriminate damage to biomolecules. ApoE4, lacking Cys, is unable to protect against oxidative damage that is commensurate with ageing.
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Affiliation(s)
- Muhammad I Abeer
- Department of Chemistry and Biochemistry, California State University Long Beach, CA, USA
| | - Abbas Abdulhasan
- Department of Chemistry and Biochemistry, California State University Long Beach, CA, USA
| | - Zahraa Haguar
- Department of Chemistry and Biochemistry, California State University Long Beach, CA, USA
| | - Vasanthy Narayanaswami
- Department of Chemistry and Biochemistry, California State University Long Beach, CA, USA
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Abstract
Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C-raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.
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Affiliation(s)
- MacRae F. Linton
- 1. Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University School of Medicine, Nashville, TN 37232
- 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Patricia G. Yancey
- 1. Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Huan Tao
- 1. Department of Medicine, Division of Cardiovascular Medicine, Atherosclerosis Research Unit, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Sean S. Davies
- 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232
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Fadaei R, Davies SS. Oxidative modification of HDL by lipid aldehydes impacts HDL function. Arch Biochem Biophys 2022; 730:109397. [PMID: 36116503 PMCID: PMC9670862 DOI: 10.1016/j.abb.2022.109397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/12/2022] [Indexed: 11/21/2022]
Abstract
Reduced levels of high-density lipoprotein (HDL) cholesterol correlate with increased risk for atherosclerotic cardiovascular diseases and HDL performs functions including reverse cholesterol transport, inhibition of lipid peroxidation, and suppression of inflammation, that would appear critical for cardioprotection. However, several large clinical trials utilizing pharmacologic interventions that elevated HDL cholesterol levels failed to provide cardioprotection to at-risk individuals. The reasons for these unexpected results have only recently begun to be elucidated. HDL cholesterol levels and HDL function can be significantly discordant, so that elevating HDL cholesterol levels may not necessarily lead to increased functional capacity, particularly under conditions that cause HDL to become oxidatively modified, resulting in HDL dysfunction. Here we review evidence that oxidative modifications of HDL, including by reactive lipid aldehydes generated by lipid peroxidation, reduce HDL functionality and that dicarbonyl scavengers that protect HDL against lipid aldehyde modification are beneficial in pre-clinical models of atherosclerotic cardiovascular disease.
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Affiliation(s)
- Reza Fadaei
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sean S Davies
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
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Espinoza-Derout J, Shao XM, Lao CJ, Hasan KM, Rivera JC, Jordan MC, Echeverria V, Roos KP, Sinha-Hikim AP, Friedman TC. Electronic Cigarette Use and the Risk of Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:879726. [PMID: 35463745 PMCID: PMC9021536 DOI: 10.3389/fcvm.2022.879726] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Electronic cigarettes or e-cigarettes are the most frequently used tobacco product among adolescents. Despite the widespread use of e-cigarettes and the known detrimental cardiac consequences of nicotine, the effects of e-cigarettes on the cardiovascular system are not well-known. Several in vitro and in vivo studies delineating the mechanisms of the impact of e-cigarettes on the cardiovascular system have been published. These include mechanisms associated with nicotine or other components of the aerosol or thermal degradation products of e-cigarettes. The increased hyperlipidemia, sympathetic dominance, endothelial dysfunction, DNA damage, and macrophage activation are prominent effects of e-cigarettes. Additionally, oxidative stress and inflammation are unifying mechanisms at many levels of the cardiovascular impairment induced by e-cigarette exposure. This review outlines the contribution of e-cigarettes in the development of cardiovascular diseases and their molecular underpinnings.
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Affiliation(s)
- Jorge Espinoza-Derout
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Xuesi M. Shao
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Candice J. Lao
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Kamrul M. Hasan
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Juan Carlos Rivera
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Maria C. Jordan
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Valentina Echeverria
- Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, United States
- Laboratorio de Neurobiología, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile
| | - Kenneth P. Roos
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Amiya P. Sinha-Hikim
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Theodore C. Friedman
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Friends Research Institute, Cerritos, CA, United States
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9
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Pradipta AR, Tanaka K. Application of Acrolein Imines to Organic Synthesis, Biofunctional Studies, and Clinical Practice. CHEM REC 2021; 21:646-662. [PMID: 33769681 DOI: 10.1002/tcr.202000146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/10/2021] [Indexed: 11/12/2022]
Abstract
N-alkyl unsaturated imines derived from acrolein, a toxin produced during oxidative stress, and biogenic alkyl amines occur naturally and are considered biologically relevant compounds. However, despite the recent conceptual and technological advances in organic synthesis, research on the new reactivity of these compounds is lacking. This personal account discusses research on the reactivity that has been overlooked in acrolein imines, including the discovery of new methods to synthesize biologically active compounds, the determination of new functions of relevant imines and their precursors, i. e., aldehydes and amines, and the application of these methods for clinical diagnosis.
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Affiliation(s)
- Ambara R Pradipta
- School of Materials and Chemical Technology, Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8552, Japan
| | - Katsunori Tanaka
- School of Materials and Chemical Technology, Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8552, Japan.,Biofunctional Synthetic Chemistry Laboratory, Cluster for Pioneering Research, RIKEN 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.,Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya Street, Kazan, 420008, Russian Federation
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10
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Khadka S, Awasthi M, Lamichhane RR, Ojha C, Mamudu HM, Lavie CJ, Daggubati R, Paul TK. The Cardiovascular Effects of Electronic Cigarettes. Curr Cardiol Rep 2021; 23:40. [PMID: 33694009 DOI: 10.1007/s11886-021-01469-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2021] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW Electronic cigarettes (e-cigarettes) are gaining rapid popularity among all age groups, especially among youth. They have evolved into technologically advanced devices capable of delivering nicotine concentration and other substances. In addition to nicotine, e-cigarettes' constituents possess variety of toxic chemicals that have adverse effects on human body. RECENT FINDINGS In recent years, steady downward trend in tobacco usage has been observed; however, e-cigarette use is on upward trend. E-cigarettes are advertised as "safer" alternatives to conventional smoking and as an aid to smoking cessation. Emerging studies have, however, shown that e-cigarettes have harmful effects on the cardiovascular system and that most of the e-cigarette users are dual users, concurrently using e-cigarettes and smoking conventional cigarettes. Despite a gap in clinical studies and randomized trials analyzing adverse cardiovascular effects of e-cigarette use, the existing literature supports that different constituents of e-cigarettes such as nicotine, carbonyls, and particulate matters carry potential risk for cardiovascular diseases (CVD) on its users.
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Affiliation(s)
- Saroj Khadka
- Department of Medicine, Division of Cardiology, East Tennessee State University, 329 N State of Franklin Rd, Johnson City, TN, 37604, USA
| | - Manul Awasthi
- Department of Health Services Management and Policy, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | | | - Chandra Ojha
- Texas Tech University of Health Sciences, El Paso, TX, USA
| | - Hadii M Mamudu
- Department of Health Services Management and Policy, College of Public Health, East Tennessee State University, Johnson City, TN, USA
| | - Carl J Lavie
- Department of Cardiology, Ochsner Clinic, New Orleans, LA, USA
| | - Ramesh Daggubati
- Division of Cardiology, West Virginia University, Morgantown, WV, USA
| | - Timir K Paul
- Department of Medicine, Division of Cardiology, East Tennessee State University, 329 N State of Franklin Rd, Johnson City, TN, 37604, USA.
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11
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Gianazza E, Brioschi M, Martinez Fernandez A, Casalnuovo F, Altomare A, Aldini G, Banfi C. Lipid Peroxidation in Atherosclerotic Cardiovascular Diseases. Antioxid Redox Signal 2021; 34:49-98. [PMID: 32640910 DOI: 10.1089/ars.2019.7955] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Atherosclerotic cardiovascular diseases (ACVDs) continue to be a primary cause of mortality worldwide in adults aged 35-70 years, occurring more often in countries with lower economic development, and they constitute an ever-growing global burden that has a considerable socioeconomic impact on society. The ACVDs encompass diverse pathologies such as coronary artery disease and heart failure (HF), among others. Recent Advances: It is known that oxidative stress plays a relevant role in ACVDs and some of its effects are mediated by lipid oxidation. In particular, lipid peroxidation (LPO) is a process under which oxidants such as reactive oxygen species attack unsaturated lipids, generating a wide array of oxidation products. These molecules can interact with circulating lipoproteins, to diffuse inside the cell and even to cross biological membranes, modifying target nucleophilic sites within biomolecules such as DNA, lipids, and proteins, and resulting in a plethora of biological effects. Critical Issues: This review summarizes the evidence of the effect of LPO in the development and progression of atherosclerosis-based diseases, HF, and other cardiovascular diseases, highlighting the role of protein adduct formation. Moreover, potential therapeutic strategies targeted at lipoxidation in ACVDs are also discussed. Future Directions: The identification of valid biomarkers for the detection of lipoxidation products and adducts may provide insights into the improvement of the cardiovascular risk stratification of patients and the development of therapeutic strategies against the oxidative effects that can then be applied within a clinical setting.
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Affiliation(s)
- Erica Gianazza
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | - Maura Brioschi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
| | | | | | | | - Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Cristina Banfi
- Proteomics Unit, Monzino Cardiology Center IRCCS, Milan, Italy
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12
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Endo R, Uchiyama K, Lim SY, Itakura M, Adachi T, Uchida K. Recognition of acrolein-specific epitopes by B cell receptors triggers an innate immune response. J Biol Chem 2021; 296:100648. [PMID: 33839149 PMCID: PMC8121969 DOI: 10.1016/j.jbc.2021.100648] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 10/25/2022] Open
Abstract
Natural antibodies, predominantly immunoglobulin M (IgM), play an important role in the defense against pathogens and in maintaining homeostasis against oxidized molecules known as oxidation-specific epitopes, such as those contained in oxidized low-density lipoproteins. However, owing to the complexity of the oxidized products, very few individual epitopes have been characterized in detail. In the present study, to identify endogenous sources of oxidation-specific epitopes, we stimulated mouse spleen and peritoneal cavity (PerC) cells in vitro with bovine serum albumin modified with a variety of lipid peroxidation-related carbonyl compounds and identified the acrolein-modified bovine serum albumin as the most efficient trigger studied for the production of IgM in PerC cells. The acrolein-specific epitopes accelerated the differentiation of B-1a cells, a fetal-derived B cell lineage, to plasma cells. In addition, acrolein-modified bovine serum albumin was specifically bound to B-1a cells, suggesting the presence of an acrolein-specific IgM-B cell receptor (BCR). A hybridoma, RE-G25, producing an acrolein-specific IgM, was established from the PerC cells and was indeed identified as a population of B cells expressing a specific IgM-BCR. In addition, we analyzed the BCR repertoire of acrolein-specific B cells and identified the most frequent IgM heavy chain gene segments of the B cells. These data established the presence of innate B cells expressing the acrolein-specific BCR and suggested that in addition to our understanding of acrolein as a toxic aldehyde, it may play a role as a trigger of the innate immune response.
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Affiliation(s)
- Ryunosuke Endo
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazuki Uchiyama
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sei-Young Lim
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Masanori Itakura
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Takahiro Adachi
- Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koji Uchida
- Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan; Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.
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13
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An Increased Plasma Level of ApoCIII-Rich Electronegative High-Density Lipoprotein May Contribute to Cognitive Impairment in Alzheimer's Disease. Biomedicines 2020; 8:biomedicines8120542. [PMID: 33256187 PMCID: PMC7761422 DOI: 10.3390/biomedicines8120542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 02/02/2023] Open
Abstract
High-density lipoprotein (HDL) plays a vital role in lipid metabolism and anti-inflammatory activities; a dysfunctional HDL impairs cholesterol efflux pathways. To understand HDL's role in patients with Alzheimer's disease (AD), we analyzed the chemical properties and function. HDL from AD patients (AD-HDL) was separated into five subfractions, H1-H5, using fast-protein liquid chromatography equipped with an anion-exchange column. Subfraction H5, defined as the most electronegative HDL, was increased 5.5-fold in AD-HDL (23.48 ± 17.83%) in comparison with the control HDL (4.24 ± 3.22%). By liquid chromatography mass spectrometry (LC/MSE), AD-HDL showed that the level of apolipoprotein (apo)CIII was elevated but sphingosine-1-phosphate (S1P)-associated apoM and anti-oxidative paraoxonase 1 (PON1) were reduced. AD-HDL showed a lower cholesterol efflux capacity that was associated with the post-translational oxidation of apoAI. Exposure of murine macrophage cell line, RAW 264.7, to AD-HDL induced a vibrant expression of ganglioside GM1 in colocalization with apoCIII on lipid rafts alongside a concomitant increase of tumor necrosis factor-α (TNF-α) detectable in the cultured medium. In conclusion, AD-HDL had a higher proportion of H5, an apoCIII-rich electronegative HDL subfraction. The associated increase in pro-inflammatory (apoCIII, TNF-α) components might favor Amyloid β assembly and neural inflammation. A compromised cholesterol efflux capacity of AD-HDL may also contribute to cognitive impairment.
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14
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Transfer and Enzyme-Mediated Metabolism of Oxidized Phosphatidylcholine and Lysophosphatidylcholine between Low- and High-Density Lipoproteins. Antioxidants (Basel) 2020; 9:antiox9111045. [PMID: 33114515 PMCID: PMC7712993 DOI: 10.3390/antiox9111045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 10/23/2020] [Indexed: 01/01/2023] Open
Abstract
Oxidized low-density lipoprotein (oxLDL) and oxidized high-density lipoprotein (oxHDL), known as risk factors for cardiovascular disease, have been observed in plasma and atheromatous plaques. In a previous study, the content of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) species stayed constant in isolated in vivo oxLDL but increased in copper-induced oxLDL in vitro. In this study, we prepared synthetic deuterium-labeled 1-palmitoyl lysoPC and palmitoyl-glutaroyl PC (PGPC), a short chain-oxPC to elucidate the metabolic fate of oxPC and lysoPC in oxLDL in the presence of HDL. When LDL preloaded with d13-lysoPC was mixed with HDL, d13-lysoPC was recovered in both the LDL and HDL fractions equally. d13-LysoPC decreased by 50% after 4 h of incubation, while d13-PC increased in both fractions. Diacyl-PC production was abolished by an inhibitor of lecithin-cholesterol acyltransferase (LCAT). When d13-PGPC-preloaded LDL was incubated with HDL, d13-PGPC was transferred to HDL in a dose-dependent manner when both LCAT and lipoprotein-associated phospholipase A2 (Lp-PLA2) were inhibited. Lp-PLA2 in both HDL and LDL was responsible for the hydrolysis of d13-PGPC. These results suggest that short chain-oxPC and lysoPC can transfer between lipoproteins quickly and can be enzymatically converted from oxPC to lysoPC and from lysoPC to diacyl-PC in the presence of HDL.
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15
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Buchanan ND, Grimmer JA, Tanwar V, Schwieterman N, Mohler PJ, Wold LE. Cardiovascular risk of electronic cigarettes: a review of preclinical and clinical studies. Cardiovasc Res 2020; 116:40-50. [PMID: 31696222 DOI: 10.1093/cvr/cvz256] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 08/08/2019] [Accepted: 10/04/2019] [Indexed: 12/13/2022] Open
Abstract
Cigarette smoking is the most preventable risk factor related to cardiovascular morbidity and mortality. Tobacco usage has declined in recent years; however, the use of alternative nicotine delivery methods, particularly e-cigarettes, has increased exponentially despite limited data on their short- and long-term safety and efficacy. Due to their unique properties, the impact of e-cigarettes on cardiovascular physiology is not fully known. Here, we summarize both preclinical and clinical data extracted from short- and long-term studies on the cardiovascular effects of e-cigarette use. Current findings support that e-cigarettes are not a harm-free alternative to tobacco smoke. However, the data are primarily derived from acute studies. The impact of chronic e-cigarette exposure is essentially unstudied. To explore the uniqueness of e-cigarettes, we contemplate the cardiovascular effects of individual e-cigarette constituents. Overall, data suggest that exposure to e-cigarettes could be a potential cardiovascular health concern. Further preclinical research and randomized trials are needed to expand basic and clinical investigations before considering e-cigarettes safe alternatives to conventional cigarettes.
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Affiliation(s)
- Nicholas D Buchanan
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Jacob A Grimmer
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Vineeta Tanwar
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Neill Schwieterman
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,College of Nursing, The Ohio State University, Columbus, OH, USA
| | - Peter J Mohler
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA
| | - Loren E Wold
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.,College of Nursing, The Ohio State University, Columbus, OH, USA.,Department of Physiology and Cell Biology, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA
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16
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He Y, Ronsein GE, Tang C, Jarvik GP, Davidson WS, Kothari V, Song HD, Segrest JP, Bornfeldt KE, Heinecke JW. Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles. Circ Res 2020; 127:1198-1210. [PMID: 32819213 DOI: 10.1161/circresaha.120.317178] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
RATIONALE HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear. OBJECTIVE To test the hypothesis that HDL's cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus. METHODS AND RESULTS We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC-but not ABCG1 CEC-of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles. CONCLUSIONS The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.
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Affiliation(s)
- Yi He
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
| | | | - Chongren Tang
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
| | - Gail P Jarvik
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
| | - W Sean Davidson
- Department of Medicine, University of Cincinnati, OH (W.S.D.)
| | - Vishal Kothari
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
| | - Hyun D Song
- Department of Medicine, Vanderbilt University, Nashville, TN (H.D.S., J.P.S.)
| | - Jere P Segrest
- Department of Medicine, Vanderbilt University, Nashville, TN (H.D.S., J.P.S.)
| | - Karin E Bornfeldt
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
| | - Jay W Heinecke
- Department of Medicine, University of Washington, Seattle (Y.H., C.T., G.P.J., V.K., K.E.B., J.W.H.)
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17
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Bein K, Birru RL, Wells H, Larkin TP, Cantrell PS, Fagerburg MV, Zeng X, Leikauf GD. Albumin Protects Lung Cells against Acrolein Cytotoxicity and Acrolein-Adducted Albumin Increases Heme Oxygenase 1 Transcripts. Chem Res Toxicol 2020; 33:1969-1979. [PMID: 32530271 DOI: 10.1021/acs.chemrestox.0c00146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Albumin is an abundant protein in the lung lining fluid that forms an interface between lung epithelial cells and the external environment. In the lung, albumin can be targeted for adduction by inhaled acrolein. Acrolein, an α,β-unsaturated aldehyde, reacts with biomolecules via Michael addition at the β-carbon or Schiff base formation at the carbonyl carbon. To gain insight into acrolein's mode of action, we investigated in vitro albumin-acrolein reactivity and the consequence of albumin adduction by acrolein on cytotoxicity and transcript changes in NCI-H441 and human airway epithelial cells (HAEC). Albumin protected NCI-H441 cells from acrolein toxicity. In addition, albumin inhibited acrolein-induced increase of transcripts associated with cellular stress response, activating transcription factor 3 (ATF3), and antioxidant response, heme oxygenase 1 (HMOX1) in HAEC cells. Acrolein-adducted albumin itself increased HMOX1 transcripts but not ATF3 transcripts. The HMOX1 transcript increase was inhibited by hydralazine, a carbonyl scavenger, suggesting that the carbonyl group of acrolein-adducted albumin mediated HMOX1 transcript increase. In acutely exposed C57BL/6J mice, bronchoalveolar lavage protein carbonylation increased. Acrolein-adducted albumin Cys34 was identified by nLC-MS/MS. These findings indicate that adduction of albumin by acrolein confers a cytoprotective function by scavenging free acrolein, decreasing a cellular stress response, and inducing an antioxidant gene response. Further, these results suggest that β-carbon reactivity may be required for acrolein's cytotoxicity and ATF3 transcript increase, and the carbonyl group of acrolein-adducted albumin can induce HMOX1 transcript increase.
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Affiliation(s)
- Kiflai Bein
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Rahel L Birru
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Heather Wells
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Theodore P Larkin
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Pamela S Cantrell
- Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Matthew V Fagerburg
- Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.,Department of Cell Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - Xuemei Zeng
- Biomedical Mass Spectrometry Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
| | - George D Leikauf
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States
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18
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Ito F, Ito T. High-Density Lipoprotein (HDL) Triglyceride and Oxidized HDL: New Lipid Biomarkers of Lipoprotein-Related Atherosclerotic Cardiovascular Disease. Antioxidants (Basel) 2020; 9:antiox9050362. [PMID: 32357465 PMCID: PMC7278571 DOI: 10.3390/antiox9050362] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/21/2020] [Accepted: 04/24/2020] [Indexed: 12/14/2022] Open
Abstract
Lipid markers are well-established predictors of vascular disease. The most frequently measured lipid markers are total cholesterol, high-density lipoprotein (HDL)-cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglyceride. HDL reduces atherosclerosis by multiple mechanisms, leading to a reduced risk of cardiovascular disease, and HDL-C, as a metric of HDL quantity, is inversely associated with cardiovascular disease, independent of LDL-C. However, the quality of the HDL appears to be more important than its quantity, because HDL loses its antiatherogenic functions due to changes in its composition and becomes “dysfunctional HDL”. Although there is evidence of the existence of “dysfunctional HDL”, biomarkers for monitoring dysfunctional HDL in clinical practice have not yet been established. In this review, we propose a new lipid panel for the assessment of dysfunctional HDL and lipoprotein-related atherosclerotic cardiovascular disease. The lipid panel includes the measurement of lipid peroxide and triglyceride contents within HDL particles.
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Affiliation(s)
- Fumiaki Ito
- The Institute of Prophylactic Pharmacology, Shinagawa, Tokyo 140-0001, Japan
- Correspondence:
| | - Tomoyuki Ito
- Physical Medicine and Rehabilitation, Tanabe Memorial Hospital, Kyotanabe-City, Kyoto 610-0331, Japan;
- Department of Rehabilitation Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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19
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May-Zhang LS, Yermalitsky V, Melchior JT, Morris J, Tallman KA, Borja MS, Pleasent T, Amarnath V, Song W, Yancey PG, Davidson WS, Linton MF, Davies SS. Modified sites and functional consequences of 4-oxo-2-nonenal adducts in HDL that are elevated in familial hypercholesterolemia. J Biol Chem 2019; 294:19022-19033. [PMID: 31666337 PMCID: PMC6916491 DOI: 10.1074/jbc.ra119.009424] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/25/2019] [Indexed: 12/18/2022] Open
Abstract
The lipid aldehyde 4-oxo-2-nonenal (ONE) is a highly reactive protein crosslinker derived from peroxidation of n-6 polyunsaturated fatty acids and generated together with 4-hydroxynonenal (HNE). Lipid peroxidation product-mediated crosslinking of proteins in high-density lipoprotein (HDL) causes HDL dysfunction and contributes to atherogenesis. Although HNE is relatively well-studied, the role of ONE in atherosclerosis and in modifying HDL is unknown. Here, we found that individuals with familial hypercholesterolemia (FH) had significantly higher ONE-ketoamide (lysine) adducts in HDL (54.6 ± 33.8 pmol/mg) than healthy controls (15.3 ± 5.6 pmol/mg). ONE crosslinked apolipoprotein A-I (apoA-I) on HDL at a concentration of > 3 mol ONE per 10 mol apoA-I (0.3 eq), which was 100-fold lower than HNE, but comparable to the potent protein crosslinker isolevuglandin. ONE-modified HDL partially inhibited HDL's ability to protect against lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) gene expression in murine macrophages. At 3 eq, ONE dramatically decreased apoA-I exchange from HDL, from ∼46.5 to ∼18.4% (p < 0.001). Surprisingly, ONE modification of HDL or apoA-I did not alter macrophage cholesterol efflux capacity. LC-MS/MS analysis revealed that Lys-12, Lys-23, Lys-96, and Lys-226 in apoA-I are modified by ONE ketoamide adducts. Compared with other dicarbonyl scavengers, pentylpyridoxamine (PPM) most efficaciously blocked ONE-induced protein crosslinking in HDL and also prevented HDL dysfunction in an in vitro model of inflammation. Our findings show that ONE-HDL adducts cause HDL dysfunction and are elevated in individuals with FH who have severe hypercholesterolemia.
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Affiliation(s)
- Linda S May-Zhang
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - Valery Yermalitsky
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | - John T Melchior
- Department of Pathology & Laboratory Medicine, University of Cincinnati, Ohio 45220
| | - Jamie Morris
- Department of Pathology & Laboratory Medicine, University of Cincinnati, Ohio 45220
| | - Keri A Tallman
- Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232
| | - Mark S Borja
- Department of Chemistry & Biochemistry, California State University East Bay, Hayward, California 94542
| | - Tiffany Pleasent
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
| | | | - Wenliang Song
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
| | - Patricia G Yancey
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
| | - W Sean Davidson
- Department of Pathology & Laboratory Medicine, University of Cincinnati, Ohio 45220
| | - MacRae F Linton
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
- Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232
| | - Sean S Davies
- Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232
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20
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Suematsu Y, Goto M, Park C, Nunes ACF, Jing W, Streja E, Rhee CM, Cruz S, Kashyap ML, Vaziri ND, Narayanaswami V, Kalantar-Zadeh K, Moradi H. Association of Serum Paraoxonase/Arylesterase Activity With All-Cause Mortality in Maintenance Hemodialysis Patients. J Clin Endocrinol Metab 2019; 104:4848-4856. [PMID: 30920627 PMCID: PMC6733492 DOI: 10.1210/jc.2019-00334] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 03/22/2019] [Indexed: 12/25/2022]
Abstract
CONTEXT In end-stage renal disease (ESRD), serum high-density lipoprotein cholesterol (HDL-C) level is not an accurate predictor of mortality, partly because it does not necessarily correlate with indices of HDL function. Paraoxonase (PON) is a major enzyme constituent of HDL and a key component of HDL antioxidant activity. Apolipoprotein A-I (Apo A-1) is the core HDL structural protein that plays a major role in various aspects of HDL function. OBJECTIVE We sought to examine PON activity and Apo A-I levels in patients with ESRD vs healthy controls. DESIGN AND SETTING PON/arylesterase activity was measured in 499 patients with maintenance hemodialysis (MHD) and 24 healthy controls with similar distributions of age, sex, and race/ethnicity. Serum acrolein-modified Apo A-I was measured in 30 patients with MHD and 10 healthy controls. MAIN OUTCOME MEASURES Multilevel Cox models were used to assess associations among PON activity, Apo A-I, and HDL-C levels with 12-month all-cause mortality. RESULTS PON activity was significantly lower in patients with MHD vs controls. Furthermore, acrolein-modified Apo A-I levels were higher in patients with MHD vs controls. In fully adjusted models, high PON activity was associated with lower 12-month mortality, whereas no difference of mortality risk was observed across HDL-C levels. The combination of high PON and low Apo A-I compared with low PON and low Apo A-I was associated with lower mortality risk. CONCLUSIONS In patients with MHD, PON activity had a stronger association with 12-month mortality than HDL-C. Future studies are needed to examine the role of these markers as potential diagnostic and therapeutic tools in ESRD.
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Affiliation(s)
- Yasunori Suematsu
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
| | - Masaki Goto
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
| | - Christina Park
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
| | - Ane C F Nunes
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
| | - WangHui Jing
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
| | - Elani Streja
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
| | - Connie M Rhee
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
| | - Siobanth Cruz
- Department of Chemistry & Biochemistry, California State University Long Beach, Long Beach, California
| | - Moti L Kashyap
- Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Long Beach, California
- University of California, Irvine, California
| | - Nosratola D Vaziri
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
| | - Vasanthy Narayanaswami
- Department of Chemistry & Biochemistry, California State University Long Beach, Long Beach, California
| | - Kamyar Kalantar-Zadeh
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
| | - Hamid Moradi
- Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, California
- Nephrology Section, Tibor Rubin VA Medical Center, Long Beach, California
- Correspondence and Reprint Requests: Hamid Moradi, MD, Department of Medicine, Nephrology Section, Long Beach VA Healthcare System, 5901 East 7th Street, Long Beach, California 90822. E-mail:
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21
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Tavori H, Fenton AM, Plubell DL, Rosario S, Yerkes E, Gasik R, Miles J, Bergstrom P, Minnier J, Fazio S, Pamir N. Elevated Lipoprotein(a) Levels Lower ABCA1 Cholesterol Efflux Capacity. J Clin Endocrinol Metab 2019; 104:4793-4803. [PMID: 31220285 PMCID: PMC6735736 DOI: 10.1210/jc.2018-02708] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 04/03/2019] [Indexed: 12/14/2022]
Abstract
CONTEXT Elevated serum lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease risk. ABCA1-mediated cholesterol efflux from macrophages may be an antiatherogenic process. Plasminogen (PLG) is a driver of ABCA1-mediated cholesterol efflux, and its action is inhibited by purified human Lp(a). OBJECTIVE To determine the effects of Lp(a) in human serum on ABCA1 cholesterol efflux. METHODS Cholesterol efflux capacity (CEC) was measured with two different cell-culture models using serum from 76 patients with either low (<50 mg/dL) or high (>50 mg/dL) Lp(a) levels. RESULTS Using cAMP-stimulated J774 macrophages or baby hamster kidney fibroblasts overexpressing human ABCA1, we show that CEC was lower in patients with high Lp(a) levels compared with patients with low levels (-30.6%, P = 0.002 vs -24.1%, P < 0.001, respectively). Total-serum CEC negatively correlated with Lp(a) levels (r = -0.433, P = 0.0007 vs r = -0.505, P = 0.0011, respectively). These negative associations persisted after adjusting for serum cholesterol, age, sex, and statin use in a multiple linear regression model (adjusted R2 = 0.413 or 0.405, respectively) and were strengthened when further adjusting for the interaction between Lp(a) and PLG levels (adjusted R2 = 0.465 and 0.409, respectively). Total-serum and isolated Lp(a) from patients with high Lp(a) inhibited PLG-mediated ABCA1 cholesterol efflux. CONCLUSION Total-serum CEC is reduced in patients with high Lp(a) levels. This is in part due to the inhibition of PLG-mediated ABCA1 cholesterol efflux by Lp(a). Our findings suggest an atherogenic role for Lp(a) through its ability to inhibit CEC.
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Affiliation(s)
- Hagai Tavori
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Alexandra M Fenton
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Deanna L Plubell
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Sara Rosario
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Elisabeth Yerkes
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Rayna Gasik
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Joshua Miles
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Paige Bergstrom
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Jessica Minnier
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Sergio Fazio
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
| | - Nathalie Pamir
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Sciences University, Portland, Oregon
- Correspondence and Reprint Requests: Nathalie Pamir, PhD, Knight Cardiovascular Institute, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97239. E-mail:
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22
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Cruz S, Narayanaswami V. Cellular Uptake and Clearance of Oxidatively-modified Apolipoprotein E3 by Cerebral Cortex Endothelial Cells. Int J Mol Sci 2019; 20:ijms20184582. [PMID: 31533203 PMCID: PMC6769588 DOI: 10.3390/ijms20184582] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/05/2019] [Accepted: 09/07/2019] [Indexed: 12/12/2022] Open
Abstract
Apolipoprotein E3 (apoE3) plays a critical role in the metabolism of lipoproteins and lowers plasma lipid levels by serving as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins and by promoting macrophage cholesterol efflux. The current study examines the effect of acrolein (an endogenously generated metabolite and an environmental pollutant) modification on the structure and function of apoE3. Acrolein modification was confirmed in Western blots by reactivity with acrolein–lysine-specific antibody and by the presence of oligomeric species due to cross-linking. LC-MS/MS analysis revealed modification of 10 out of 12 lysines in apoE3, with Nε-(3-methylpyridinium)-lysine being the predominant form of modification, and Lys75 being a ‘hot spot’ in terms of susceptibility to oxidation. Circular dichroism spectroscopy showed no major change in overall secondary structure compared to unmodified apoE3. Reconstituted high density lipoprotein (HDL) bearing acrolein modified apoE3 showed loss of binding to soluble LDLr; however, incubation with mouse endothelioma bEnd.3 cells showed that it was internalized. Incubation with excess LDL did not abolish cellular uptake of acrolein modified apoE3, suggesting alternative mechanism(s) not involving LDLr. Incubation with anti-CD36 antibody did not show a decrease in internalization while incubation with anti- lectin-like oxidized LDL receptor 1 (LOX1) showed partial internalization. However, incubation with anti-scavenger receptor class B type I (SRB1) antibody abolished internalization of acrolein modified apoE3. Taken together, our studies suggest that acrolein modification of apoE3 at lysine residues leads to increase in net negative charge, and as a consequence, results in clearance by LOX1 and SRB1 on endothelial cells. Overall, oxidative modification of apoE3 likely impairs its role in regulating plasma cholesterol homeostasis, eventually leading to lipid disorders.
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Affiliation(s)
- Siobanth Cruz
- Department of Chemistry and Biochemistry 1250 Bellflower Blvd., California State University Long Beach, Long Beach, CA 90840, USA.
| | - Vasanthy Narayanaswami
- Department of Chemistry and Biochemistry 1250 Bellflower Blvd., California State University Long Beach, Long Beach, CA 90840, USA.
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23
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Schill RL, Knaack DA, Powers HR, Chen Y, Yang M, Schill DJ, Silverstein RL, Sahoo D. Modification of HDL by reactive aldehydes alters select cardioprotective functions of HDL in macrophages. FEBS J 2019; 287:695-707. [PMID: 31386799 DOI: 10.1111/febs.15034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 06/23/2019] [Accepted: 08/02/2019] [Indexed: 01/02/2023]
Abstract
While increased levels of high-density lipoprotein (HDL)-cholesterol correlate with protection against cardiovascular disease, recent findings demonstrate that HDL function, rather than HDL-cholesterol levels, may be a better indicator of cardiovascular risk. One mechanism by which HDL function can be compromised is through modification by reactive aldehydes such as acrolein (Acro), 4-hydroxynonenal, and malondialdehyde (MDA). In this study, we tested the hypothesis that modification of HDL with reactive aldehydes would impair HDL's athero-protective functions in macrophages. Compared to native HDL, Acro- and MDA-modified HDL have impaired abilities to promote migration of primary peritoneal macrophages isolated from C57BL6/J mice. Incubation of macrophages with MDA-HDL also led to an increased ability to generate reactive oxygen species. Our studies revealed that the changes in HDL function following aldehyde modification are likely not through activation of canonical nuclear factor-kappa B signaling pathways. Consistent with this finding, treatment of either noncholesterol-loaded macrophages or foam cells with modified forms of HDL does not lead to significant changes in expression levels of inflammatory markers. Importantly, our data also demonstrate that changes in HDL function are dependent on the type of modification present on the HDL particle. Our findings suggest that modification of HDL with reactive aldehydes can impair some, but not all, of HDL's athero-protective functions in macrophages.
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Affiliation(s)
- Rebecca L Schill
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Darcy A Knaack
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Hayley R Powers
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yiliang Chen
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA
| | - Moua Yang
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.,Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Daniel J Schill
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Roy L Silverstein
- Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.,Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Daisy Sahoo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.,Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.,Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA
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24
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Zirak MR, Mehri S, Karimani A, Zeinali M, Hayes AW, Karimi G. Mechanisms behind the atherothrombotic effects of acrolein, a review. Food Chem Toxicol 2019; 129:38-53. [DOI: 10.1016/j.fct.2019.04.034] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 03/18/2019] [Accepted: 04/18/2019] [Indexed: 12/31/2022]
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25
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Kishimoto A, Nomura S, Tanaka K. Chemical Sensing of Acrolein-Amine Conjugates for Food Quality Control: A Case Study of Milk Products. BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN 2019. [DOI: 10.1246/bcsj.20190010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Arisa Kishimoto
- Biofunctional Synthetic Chemistry Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Shogo Nomura
- Biofunctional Synthetic Chemistry Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Katsunori Tanaka
- Biofunctional Synthetic Chemistry Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya street, Kazan 420008, Russia
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26
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Badea M, Gaman L, Delia C, Ilea A, Leașu F, Henríquez-Hernández LA, Luzardo OP, Rădoi M, Rogozea L. Trends of Lipophilic, Antioxidant and Hematological Parameters Associated with Conventional and Electronic Smoking Habits in Middle-Age Romanians. J Clin Med 2019; 8:E665. [PMID: 31083602 PMCID: PMC6571835 DOI: 10.3390/jcm8050665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 05/01/2019] [Accepted: 05/09/2019] [Indexed: 01/15/2023] Open
Abstract
It is known that cigarette smoking is correlated with medical associated inquires. New electronic cigarettes are intensively advertised as an alternative to conventional smoking, but only a few studies demonstrate their harmful potential. A cross-sectional study was designed using 150 subjects from Brasov (Romania), divided into three groups: non-smokers (NS = 58), conventional cigarettes smokers (CS = 58) and electronic cigarettes users (ECS = 34). The aim of this study was to determine levels of some plasma lipophilic and hematological components, and the total antioxidant status that could be associated with the smoking status of the subjects. Serum low density lipoproteins (LDL) cholesterol increased significantly for ECS participants versus NS group (18.9% difference) (p < 0.05). Also, the CS group is characterized by an increase of serum LDL cholesterol (7.9% difference vs. NS), but with no significant statistical difference. The variation of median values of serum very low density lipoproteins (VLDL) was in order NS < ECS < CS, with statistical difference between NS and CS groups (34.6% difference; p = 0.023). When comparing the antioxidant status of the three groups, significant differences (p < 0.05) were obtained between NS vs. CS and NS vs. ECS. Similar behavior was identified for CS and ECS. Statistically significant changes (p < 0.0001) for both vitamin A and vitamin E were identified in the blood of NS vs. CS and NS vs. ECS, and also when comparing vitamin A in the blood of the CS group versus the ECS group (p < 0.05). When all groups were compared, the difference in the white blood cell (WBC) was (p = 0.008). A slight increase in the red blood cell (RBC) count was observed, but with no statistical difference between groups. These results indicated that conventional cigarette and e-cigarette usage promotes the production of excess reactive oxygen species, involving different pathways, different antioxidants and bioactive molecules.
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Affiliation(s)
- Mihaela Badea
- Faculty of Medicine, Transilvania University of Brasov, Brasov 500019, Romania.
| | - Laura Gaman
- "Carol Davila" University of Medicine and Pharmacy, Bucharest 050474, Romania.
| | - Corina Delia
- National Institute for Mother and Child Health "Alessandrescu-Rusescu", Bucharest 20395, Romania.
| | - Anca Ilea
- Faculty of Medicine, Transilvania University of Brasov, Brasov 500019, Romania.
| | - Florin Leașu
- Faculty of Medicine, Transilvania University of Brasov, Brasov 500019, Romania.
| | - Luis Alberto Henríquez-Hernández
- Toxicology Unit, Clinical Sciences Department, Universidad de Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe, s/n, 35019 Las Palmas de Gran Canaria, Spain.
| | - Octavio P Luzardo
- Toxicology Unit, Clinical Sciences Department, Universidad de Las Palmas de Gran Canaria, Paseo Blas Cabrera Felipe, s/n, 35019 Las Palmas de Gran Canaria, Spain.
| | - Mariana Rădoi
- Faculty of Medicine, Transilvania University of Brasov, Brasov 500019, Romania.
| | - Liliana Rogozea
- Faculty of Medicine, Transilvania University of Brasov, Brasov 500019, Romania.
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27
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Pamir N, Pan C, Plubell DL, Hutchins PM, Tang C, Wimberger J, Irwin A, Vallim TQDA, Heinecke JW, Lusis AJ. Genetic control of the mouse HDL proteome defines HDL traits, function, and heterogeneity. J Lipid Res 2019; 60:594-608. [PMID: 30622162 PMCID: PMC6399512 DOI: 10.1194/jlr.m090555] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/10/2018] [Indexed: 12/30/2022] Open
Abstract
HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local cis-acting regulation, termed cis-protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL’s properties, such as protection against CAD.
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Affiliation(s)
- Nathalie Pamir
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR
| | - Calvin Pan
- Departments of Genetics University of California at Los Angeles, Los Angeles, CA
| | - Deanna L Plubell
- Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR
| | | | - Chongren Tang
- Department of Medicine University of Washington, Seattle, WA
| | - Jake Wimberger
- Department of Medicine University of Washington, Seattle, WA
| | - Angela Irwin
- Department of Medicine University of Washington, Seattle, WA
| | | | - Jay W Heinecke
- Department of Medicine University of Washington, Seattle, WA
| | - Aldons J Lusis
- Departments of Genetics University of California at Los Angeles, Los Angeles, CA
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28
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Peck MJ, Sanders EB, Scherer G, Lüdicke F, Weitkunat R. Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products. Biomarkers 2018; 23:213-244. [PMID: 29297706 DOI: 10.1080/1354750x.2017.1419284] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Context: One approach to reducing the harm caused by cigarette smoking, at both individual and population level, is to develop, assess and commercialize modified risk alternatives that adult smokers can switch to. Studies to demonstrate the exposure and risk reduction potential of such products generally involve the measuring of biomarkers, of both exposure and effect, sampled in various biological matrices.Objective: In this review, we detail the pros and cons for using several biomarkers as indicators of effects of changing from conventional cigarettes to modified risk products.Materials and methods: English language publications between 2008 and 2017 were retrieved from PubMed using the same search criteria for each of the 25 assessed biomarkers. Nine exclusion criteria were applied to exclude non-relevant publications.Results: A total of 8876 articles were retrieved (of which 7476 were excluded according to the exclusion criteria). The literature indicates that not all assessed biomarkers return to baseline levels following smoking cessation during the study periods but that nine had potential for use in medium to long-term studies.Discussion and conclusion: In clinical studies, it is important to choose biomarkers that show the biological effect of cessation within the duration of the study.
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Affiliation(s)
| | | | | | - Frank Lüdicke
- Research & Development, Philip Morris International, Neuchâtel, Switzerland
| | - Rolf Weitkunat
- Research & Development, Philip Morris International, Neuchâtel, Switzerland
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29
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Nègre-Salvayre A, Garoby-Salom S, Swiader A, Rouahi M, Pucelle M, Salvayre R. Proatherogenic effects of 4-hydroxynonenal. Free Radic Biol Med 2017; 111:127-139. [PMID: 28040472 DOI: 10.1016/j.freeradbiomed.2016.12.038] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 12/22/2016] [Accepted: 12/24/2016] [Indexed: 01/08/2023]
Abstract
4-hydroxy-2-nonenal (HNE) is a α,β-unsaturated hydroxyalkenal generated by peroxidation of n-6 polyunsaturated fatty acid. This reactive carbonyl compound exhibits a huge number of biological properties that result mainly from the formation of HNE-adducts on free amino groups and thiol groups in proteins. In the vascular system, HNE adduct accumulation progressively leads to cellular dysfunction and tissue damages that are involved in the progression of atherosclerosis and related diseases. HNE contributes to the atherogenicity of oxidized LDL, by forming HNE-apoB adducts that deviate the LDL metabolism to the scavenger receptor pathway of macrophagic cells, and lead to the formation of foam cells. HNE activates transcription factors (Nrf2, NF-kappaB) that (dys)regulate various cellular responses ranging from hormetic and survival signaling at very low concentrations, to inflammatory and apoptotic effects at higher concentrations. Among a variety of cellular targets, HNE can modify signaling proteins involved in atherosclerotic plaque remodeling, particularly growth factor receptors (PDGFR, EGFR), cell cycle proteins, mitochondrial and endoplasmic reticulum components or extracellular matrix proteins, which progressively alters smooth muscle cell proliferation, angiogenesis and induces apoptosis. HNE adducts accumulate in the lipidic necrotic core of advanced atherosclerotic lesions, and may locally contribute to macrophage and smooth muscle cell apoptosis, which may induce plaque destabilization and rupture, thereby increasing the risk of athero-thrombotic events.
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Affiliation(s)
| | | | | | | | | | - Robert Salvayre
- Inserm UMR-1048, France; University of Toulouse, Faculty of Medicine, Biochemistry Dept, Toulouse, France; CHU Toulouse, Rangueil, Toulouse, France
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30
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Vistoli G, Mantovani C, Gervasoni S, Pedretti A, Aldini G. Key factors regulating protein carbonylation by α,β unsaturated carbonyls: A structural study based on a retrospective meta-analysis. Biophys Chem 2017; 230:20-26. [PMID: 28851547 DOI: 10.1016/j.bpc.2017.08.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/11/2017] [Accepted: 08/13/2017] [Indexed: 01/20/2023]
Abstract
Protein carbonylation represents one of the most important oxidative-based modifications involving nucleophilic amino acids and affecting protein folding and function. Protein carbonylation is induced by electrophilic carbonyl species and is an highly selective process since few nucleophilic residues are carbonylated within each protein. While considering the great interest for protein carbonylation, few studies investigated the factors which render a nucleophilic residue susceptible to carbonylation. Hence, the present study is aimed to delve into the factors which modulate the reactivity of cysteine, histidine and lysine residues towards α,β unsaturated carbonyls by a retrospective analysis of the available studies which identified the adducted residues for proteins, the structure of which was resolved. Such an analysis involved different parameters including exposure, nucleophilicity, surrounding residues and capacity to attract carbonyl species (as derived by docking simulations). The obtained results allowed a meaningful clustering of the analyzed proteins suggesting that on average carbonylation selectivity increases with protein size. The comparison between adducted and unreactive residues revealed differences in all monitored parameters which are markedly more pronounced for cysteines compared to lysines and histidines. Overall, these results suggest that cysteine's carbonylation is a finely (and reasonably purposely) modulated process, while the carbonylation of lysines and histidines seems to be a fairly random event in which limited differences influence their reactivity.
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Affiliation(s)
- Giulio Vistoli
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
| | - Chiara Mantovani
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
| | - Silvia Gervasoni
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
| | - Alessandro Pedretti
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
| | - Giancarlo Aldini
- Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
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31
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Pamir N, Hutchins PM, Ronsein GE, Wei H, Tang C, Das R, Vaisar T, Plow E, Schuster V, Koschinsky ML, Reardon CA, Weinberg R, Dichek DA, Marcovina S, Getz GS, Heinecke JW. Plasminogen promotes cholesterol efflux by the ABCA1 pathway. JCI Insight 2017; 2:92176. [PMID: 28768900 DOI: 10.1172/jci.insight.92176] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 06/20/2017] [Indexed: 12/20/2022] Open
Abstract
Using genetic and biochemical approaches, we investigated proteins that regulate macrophage cholesterol efflux capacity (CEC) and ABCA1-specific CEC (ABCA1 CEC), 2 functional assays that predict cardiovascular disease (CVD). Macrophage CEC and the concentration of HDL particles were markedly reduced in mice deficient in apolipoprotein A-I (APOA1) or apolipoprotein E (APOE) but not apolipoprotein A-IV (APOA4). ABCA1 CEC was markedly reduced in APOA1-deficient mice but was barely affected in mice deficient in APOE or APOA4. High-resolution size-exclusion chromatography of plasma produced 2 major peaks of ABCA1 CEC activity. The early-eluting peak, which coeluted with HDL, was markedly reduced in APOA1- or APOE-deficient mice. The late-eluting peak was modestly reduced in APOA1-deficient mice but little affected in APOE- or APOA4-deficient mice. Ion-exchange chromatography and shotgun proteomics suggested that plasminogen (PLG) accounted for a substantial fraction of the ABCA1 CEC activity in the peak not associated with HDL. Human PLG promoted cholesterol efflux by the ABCA1 pathway, and PLG-dependent efflux was inhibited by lipoprotein(a) [Lp(a)]. Our observations identify APOA1, APOE, and PLG as key determinants of CEC. Because PLG and Lp(a) associate with human CVD risk, interplay among the proteins might affect atherosclerosis by regulating cholesterol efflux from macrophages.
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Affiliation(s)
- Nathalie Pamir
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Patrick M Hutchins
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | | | - Hao Wei
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Chongren Tang
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Riku Das
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Tomas Vaisar
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Edward Plow
- Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Volker Schuster
- Hospital for Children and Adolescents, Medical Faculty of Leipzig University, Leipzig, Germany
| | - Marlys L Koschinsky
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | | | - Richard Weinberg
- Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - David A Dichek
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Santica Marcovina
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Godfrey S Getz
- Department of Pathology, University of Chicago, Chicago, Illinois, USA
| | - Jay W Heinecke
- Department of Medicine, University of Washington, Seattle, Washington, USA
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Teng N, Maghzal GJ, Talib J, Rashid I, Lau AK, Stocker R. The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture. Redox Rep 2016; 22:51-73. [PMID: 27884085 PMCID: PMC6837458 DOI: 10.1080/13510002.2016.1256119] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Atherosclerosis is the main pathophysiological process underlying coronary artery disease (CAD). Acute complications of atherosclerosis, such as myocardial infarction, are caused by the rupture of vulnerable atherosclerotic plaques, which are characterized by thin, highly inflamed, and collagen-poor fibrous caps. Several lines of evidence mechanistically link the heme peroxidase myeloperoxidase (MPO), inflammation as well as acute and chronic manifestations of atherosclerosis. MPO and MPO-derived oxidants have been shown to contribute to the formation of foam cells, endothelial dysfunction and apoptosis, the activation of latent matrix metalloproteinases, and the expression of tissue factor that can promote the development of vulnerable plaque. As such, detection, quantification and imaging of MPO mass and activity have become useful in cardiac risk stratification, both for disease assessment and in the identification of patients at risk of plaque rupture. This review summarizes the current knowledge about the role of MPO in CAD with a focus on its possible roles in plaque rupture and recent advances to quantify and image MPO in plasma and atherosclerotic plaques.
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Affiliation(s)
- Nathaniel Teng
- a Vascular Biology Division , Victor Chang Cardiac Research Institute , Darlinghurst , New South Wales , Australia.,b Department of Cardiology , Prince of Wales Hospital , Randwick , New South Wales , Australia
| | - Ghassan J Maghzal
- a Vascular Biology Division , Victor Chang Cardiac Research Institute , Darlinghurst , New South Wales , Australia
| | - Jihan Talib
- a Vascular Biology Division , Victor Chang Cardiac Research Institute , Darlinghurst , New South Wales , Australia
| | - Imran Rashid
- a Vascular Biology Division , Victor Chang Cardiac Research Institute , Darlinghurst , New South Wales , Australia
| | - Antony K Lau
- b Department of Cardiology , Prince of Wales Hospital , Randwick , New South Wales , Australia.,c Faculty of Medicine , University of New South Wales , Sydney , New South Wales , Australia
| | - Roland Stocker
- a Vascular Biology Division , Victor Chang Cardiac Research Institute , Darlinghurst , New South Wales , Australia.,d School of Medical Sciences , University of New South Wales , Sydney , New South Wales , Australia
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Burcham PC. Acrolein and Human Disease: Untangling the Knotty Exposure Scenarios Accompanying Several Diverse Disorders. Chem Res Toxicol 2016; 30:145-161. [DOI: 10.1021/acs.chemrestox.6b00310] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Philip C. Burcham
- Pharmacology, Pharmacy & Anaesthesiology Unit, School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia 6007, Australia
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Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly. Mol Cell Biol 2016; 36:2995-3008. [PMID: 27669733 DOI: 10.1128/mcb.00448-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/14/2016] [Indexed: 01/29/2023] Open
Abstract
Acrolein is a major component of cigarette smoke and cooking fumes. Previously, we reported that acrolein compromises chromatin assembly; however, underlying mechanisms have not been defined. Here, we report that acrolein reacts with lysine residues, including lysines 5 and 12, sites important for chromatin assembly, on histone H4 in vitro and in vivo Acrolein-modified histones are resistant to acetylation, suggesting that the reduced H4K12 acetylation that occurs following acrolein exposure is probably due to the formation of acrolein-histone lysine adducts. Accordingly, the association of H3/H4 with the histone chaperone ASF1 and importin 4 is disrupted and the translocation of green fluorescent protein-tagged H3 is inhibited in cells exposed to acrolein. Interestingly, in vitro plasmid supercoiling assays revealed that treatment of either histones or ASF1 with acrolein has no effect on the formation of plasmid supercoiling, indicating that acrolein-protein adduct formation itself does not directly interfere with nucleosome assembly. Notably, exposure of histones to acrolein prior to histone acetylation leads to the inhibition of remodeling and spacing factor chromatin assembly, which requires acetylated histones for efficient assembly. These results suggest that acrolein compromises chromatin assembly by reacting with histone lysine residues at the sites critical for chromatin assembly and prevents these sites from physiological modifications.
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Takamatsu M, Fukase K, Oka R, Kitazume S, Taniguchi N, Tanaka K. A Reduction-Based Sensor for Acrolein Conjugates with the Inexpensive Nitrobenzene as an Alternative to Monoclonal Antibody. Sci Rep 2016; 6:35872. [PMID: 27782170 PMCID: PMC5080631 DOI: 10.1038/srep35872] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/05/2016] [Indexed: 11/21/2022] Open
Abstract
Acrolein, a highly toxic α, β-unsaturated aldehyde, has been a longstanding key biomarker associated with a range of disorders related to oxidative stresses. One of the most promising methods for detecting acrolein involves the use of antibodies that can recognize the acrolein-lysine conjugate, 3-formyl-3, 4-dehydropiperidines (FDP), within oxidatively stressed cells and tissues from various disease states. We have uncovered here that FDP could reduce nitroarenes in high yields at 100 °C in the presence of excess CaCl2 as a Lewis acid promoter. This unique transformation allowed for the development of a de novo method for detecting levels of FDPs generated from proteins in urine or blood serum samples. Thus we successfully converted a non-fluorescent and inexpensive 4-nitrophthalonitrile probe to the corresponding fluorescent aniline, thereby constituting the concept of fluorescent switching. Its sensitivity level (0.84 nmol/mL) is more than that of ELISA assays (3.13 nmol/mL) and is already equally reliable and reproducible at this early stage of development. More importantly, this method is cost effective and simple to operate, requiring only mixing of samples with a kit solution. Our method thus possesses potential as a future alternative to the more costly and operatively encumbered conventional antibody-based methods.
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Affiliation(s)
- Masayuki Takamatsu
- Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Department of Chemistry Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
| | - Koichi Fukase
- Department of Chemistry Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
| | - Ritsuko Oka
- Disease Glycomics Team, Global Research Cluster, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Shinobu Kitazume
- Disease Glycomics Team, Global Research Cluster, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Naoyuki Taniguchi
- Disease Glycomics Team, Global Research Cluster, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Katsunori Tanaka
- Biofunctional Synthetic Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
- Biofunctional Chemistry Laboratory, A. Butlerov Institute of Chemistry, Kazan Federal University, 18 Kremlyovskaya street, Kazan 420008, Russia
- Japan Science and Technology Agency-PRESTO, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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36
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Gogonea V. Structural Insights into High Density Lipoprotein: Old Models and New Facts. Front Pharmacol 2016; 6:318. [PMID: 26793109 PMCID: PMC4709926 DOI: 10.3389/fphar.2015.00318] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 12/22/2015] [Indexed: 11/13/2022] Open
Abstract
The physiological link between circulating high density lipoprotein (HDL) levels and cardiovascular disease is well-documented, albeit its intricacies are not well-understood. An improved appreciation of HDL function and overall role in vascular health and disease requires at its foundation a better understanding of the lipoprotein's molecular structure, its formation, and its process of maturation through interactions with various plasma enzymes and cell receptors that intervene along the pathway of reverse cholesterol transport. This review focuses on summarizing recent developments in the field of lipid free apoA-I and HDL structure, with emphasis on new insights revealed by newly published nascent and spherical HDL models constructed by combining low resolution structures obtained from small angle neutron scattering (SANS) with contrast variation and geometrical constraints derived from hydrogen-deuterium exchange (HDX), crosslinking mass spectrometry, electron microscopy, Förster resonance energy transfer, and electron spin resonance. Recently published low resolution structures of nascent and spherical HDL obtained from SANS with contrast variation and isotopic labeling of apolipoprotein A-I (apoA-I) will be critically reviewed and discussed in terms of how they accommodate existing biophysical structural data from alternative approaches. The new low resolution structures revealed and also provided some answers to long standing questions concerning lipid organization and particle maturation of lipoproteins. The review will discuss the merits of newly proposed SANS based all atom models for nascent and spherical HDL, and compare them with accepted models. Finally, naturally occurring and bioengineered mutations in apoA-I, and their impact on HDL phenotype, are reviewed and discuss together with new therapeutics employed for restoring HDL function.
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Affiliation(s)
- Valentin Gogonea
- Department of Chemistry, Cleveland State UniversityCleveland, OH, USA; Departments of Cellular and Molecular Medicine and the Center for Cardiovascular Diagnostics and Prevention, Cleveland ClinicCleveland, OH, USA
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Pamir N, Hutchins P, Ronsein G, Vaisar T, Reardon CA, Getz GS, Lusis AJ, Heinecke JW. Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol efflux capacity via the ABCA1 pathway. J Lipid Res 2015; 57:246-57. [PMID: 26673204 PMCID: PMC4727420 DOI: 10.1194/jlr.m063701] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Indexed: 12/15/2022] Open
Abstract
Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL’s size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL’s content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL’s content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL’s ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL’s APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages.
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Affiliation(s)
- Nathalie Pamir
- Department of Medicine, University of Washington, Seattle, WA
| | | | | | - Tomas Vaisar
- Department of Medicine, University of Washington, Seattle, WA
| | | | - Godfrey S Getz
- Department of Pathology, University of Chicago, Chicago, IL
| | - Aldons J Lusis
- Department of Genetics, University of California at Los Angeles, Los Angeles, CA
| | - Jay W Heinecke
- Department of Medicine, University of Washington, Seattle, WA
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Chadwick AC, Holme RL, Chen Y, Thomas MJ, Sorci-Thomas MG, Silverstein RL, Pritchard KA, Sahoo D. Acrolein impairs the cholesterol transport functions of high density lipoproteins. PLoS One 2015; 10:e0123138. [PMID: 25849485 PMCID: PMC4388475 DOI: 10.1371/journal.pone.0123138] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 02/17/2015] [Indexed: 12/22/2022] Open
Abstract
High density lipoproteins (HDL) are considered athero-protective, primarily due to their role in reverse cholesterol transport, where they transport cholesterol from peripheral tissues to the liver for excretion. The current study was designed to determine the impact of HDL modification by acrolein, a highly reactive aldehyde found in high abundance in cigarette smoke, on the cholesterol transport functions of HDL. HDL was chemically-modified with acrolein and immunoblot and mass spectrometry analyses confirmed apolipoprotein crosslinking, as well as acrolein adducts on apolipoproteins A-I and A-II. The ability of acrolein-modified HDL (acro-HDL) to serve as an acceptor of free cholesterol (FC) from COS-7 cells transiently expressing SR-BI was significantly decreased. Further, in contrast to native HDL, acro-HDL promotes higher neutral lipid accumulation in murine macrophages as judged by Oil Red O staining. The ability of acro-HDL to mediate efficient selective uptake of HDL-cholesteryl esters (CE) into SR-BI-expressing cells was reduced compared to native HDL. Together, the findings from our studies suggest that acrolein modification of HDL produces a dysfunctional particle that may ultimately promote atherogenesis by impairing functions that are critical in the reverse cholesterol transport pathway.
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Affiliation(s)
- Alexandra C. Chadwick
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Rebecca L. Holme
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Yiliang Chen
- Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Michael J. Thomas
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Mary G. Sorci-Thomas
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Roy L. Silverstein
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Kirkwood A. Pritchard
- Department of Surgery, Children’s Research Institute, Milwaukee, Wisconsin, United States of America
| | - Daisy Sahoo
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- * E-mail:
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Tsutsui A, Pradipta AR, Saigitbatalova E, Kurbangalieva A, Tanaka K. Exclusive formation of imino[4 + 4]cycloaddition products with biologically relevant amines: plausible candidates for acrolein biomarkers and biofunctional modulators. MEDCHEMCOMM 2015. [DOI: 10.1039/c4md00383g] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
We synthetically demonstrate that eight-membered heterocycles are the exclusive products of the reaction of acrolein with biologically relevant amines via an imino[4 + 4]cycloaddition.
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Affiliation(s)
- Ayumi Tsutsui
- Biofunctional Synthetic Chemistry Laboratory
- RIKEN
- Wako-shi
- Japan
| | | | - Elena Saigitbatalova
- Biofunctional Chemistry Laboratory
- A. Butlerov Institute of Chemistry
- Kazan Federal University
- Kazan 420008
- Russia
| | - Almira Kurbangalieva
- Biofunctional Chemistry Laboratory
- A. Butlerov Institute of Chemistry
- Kazan Federal University
- Kazan 420008
- Russia
| | - Katsunori Tanaka
- Biofunctional Synthetic Chemistry Laboratory
- RIKEN
- Wako-shi
- Japan
- Biofunctional Chemistry Laboratory
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40
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Imino [4+4] cycloaddition products as exclusive and biologically relevant acrolein-amine conjugates are intermediates of 3-formyl-3,4-dehydropiperidine (FDP), an acrolein biomarker. Bioorg Med Chem 2014; 22:6380-6. [DOI: 10.1016/j.bmc.2014.09.045] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/17/2014] [Accepted: 09/22/2014] [Indexed: 12/16/2022]
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Bounafaa A, Berrougui H, Ikhlef S, Essamadi A, Nasser B, Bennis A, Yamoul N, Ghalim N, Khalil A. Alteration of HDL functionality and PON1 activities in acute coronary syndrome patients. Clin Biochem 2014; 47:318-25. [PMID: 25218815 DOI: 10.1016/j.clinbiochem.2014.09.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 07/29/2014] [Accepted: 08/16/2014] [Indexed: 01/26/2023]
Abstract
OBJECTIVE The functionality of HDL has been suggested as an important factor in the prevention of cardiovascular and coronary artery diseases. The objective of the present study was to investigate the functionality of HDL and the factors that may affect the anti-atherogenic properties of HDL in ACS patients. METHODS AND RESULTS One hundred healthy subjects and 205 ACS patients were recruited. HDL functionality was evaluated by measuring their capacity to mediate cholesterol efflux from J774 macrophages. Oxidative stress status was determined by measuring plasma malondialdehyde (MDA), protein carbonyl, and vitamin E levels by HPLC. The PON1 Q192R polymorphism status and PON1 paraoxonase and arylesterase activities of the healthy subjects and ACS patients were also determined. The HDL of ACS patients displayed a limited capacity to mediate cholesterol efflux, especially via the ABCA1-pathway. MDA (7.06±0.29 μM) and protein carbonyl (9.29±0.26 μM) levels were significantly higher in ACS patients than in healthy subjects (2.29±0.21 μM and 3.07±0.17 μM, respectively, p<0.0001), while α- and γ-tocopherol (vitamin E) levels in ACS patients were 8-fold (p<0.001) and 2-fold (p<0.05) lower than in healthy subjects. Paraoxonase, arylesterase and HDL-corrected PON1 activities (PON1 activity/HDL ratio) were significantly lower in ACS patients. Logistic regression analyses showed that high PON1 paraoxonase and arylesterase activities had a significant protective effect (OR=0.413, CI 0.289-0.590, p<0.001; OR=0.232 CI 0.107-0.499, p<0.001, respectively) even when adjusted for HDL level, age, BMI, and PON1 polymorphism. CONCLUSION The results of the present study showed that the functionality of HDL is impaired in ACS patients and that the impairment may be due to oxidative stress and an alteration of PON1 activities.
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Affiliation(s)
- Abdelghani Bounafaa
- Laboratory of Biochemistry & Neuroscience, Applied Biochemistry and Toxicology Team, Hassan I University, Faculty of Sciences and Technology, Settat, Morocco; Department of Biology, Polydisciplinary Faculty, Sultan Moulay Sliman University, Beni-Mellal, Morocco; Laboratory of Biochemistry, Pasteur Institute of Morocco, Casablanca, Morocco; Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Hicham Berrougui
- Department of Biology, Polydisciplinary Faculty, Sultan Moulay Sliman University, Beni-Mellal, Morocco; Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Souade Ikhlef
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada
| | - Abdelkhalid Essamadi
- Laboratory of Biochemistry & Neuroscience, Applied Biochemistry and Toxicology Team, Hassan I University, Faculty of Sciences and Technology, Settat, Morocco
| | - Boubker Nasser
- Laboratory of Biochemistry & Neuroscience, Applied Biochemistry and Toxicology Team, Hassan I University, Faculty of Sciences and Technology, Settat, Morocco
| | - Ahmed Bennis
- Cardiology Service, Ibn Rochd University Hospital Center, Casablanca, Morocco
| | - Najoua Yamoul
- Cardiology Service, Ibn Rochd University Hospital Center, Casablanca, Morocco
| | - Noreddine Ghalim
- Laboratory of Biochemistry, Pasteur Institute of Morocco, Casablanca, Morocco
| | - Abdelouahed Khalil
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, Quebec, Canada.
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DeJarnett N, Conklin DJ, Riggs DW, Myers JA, O'Toole TE, Hamzeh I, Wagner S, Chugh A, Ramos KS, Srivastava S, Higdon D, Tollerud DJ, DeFilippis A, Becher C, Wyatt B, McCracken J, Abplanalp W, Rai SN, Ciszewski T, Xie Z, Yeager R, Prabhu SD, Bhatnagar A. Acrolein exposure is associated with increased cardiovascular disease risk. J Am Heart Assoc 2014; 3:jah3635. [PMID: 25099132 PMCID: PMC4310380 DOI: 10.1161/jaha.114.000934] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Acrolein is a reactive aldehyde present in high amounts in coal, wood, paper, and tobacco smoke. It is also generated endogenously by lipid peroxidation and the oxidation of amino acids by myeloperoxidase. In animals, acrolein exposure is associated with the suppression of circulating progenitor cells and increases in thrombosis and atherogenesis. The purpose of this study was to determine whether acrolein exposure in humans is also associated with increased cardiovascular disease (CVD) risk. Methods and Results Acrolein exposure was assessed in 211 participants of the Louisville Healthy Heart Study with moderate to high (CVD) risk by measuring the urinary levels of the major acrolein metabolite—3‐hydroxypropylmercapturic acid (3‐HPMA). Generalized linear models were used to assess the association between acrolein exposure and parameters of CVD risk, and adjusted for potential demographic confounders. Urinary 3‐HPMA levels were higher in smokers than nonsmokers and were positively correlated with urinary cotinine levels. Urinary 3‐HPMA levels were inversely related to levels of both early (AC133+) and late (AC133−) circulating angiogenic cells. In smokers as well as nonsmokers, 3‐HPMA levels were positively associated with both increased levels of platelet–leukocyte aggregates and the Framingham Risk Score. No association was observed between 3‐HPMA and plasma fibrinogen. Levels of C‐reactive protein were associated with 3‐HPMA levels in nonsmokers only. Conclusions Regardless of its source, acrolein exposure is associated with platelet activation and suppression of circulating angiogenic cell levels, as well as increased CVD risk.
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Affiliation(s)
- Natasha DeJarnett
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville, KY (N.D.J., D.J.T., R.Y.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Daniel J Conklin
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Daniel W Riggs
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - John A Myers
- Department of Pediatrics, University of Louisville, Louisville, KY (J.A.M.)
| | - Timothy E O'Toole
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Ihab Hamzeh
- Baylor College of Medicine, Houston, TX (I.H.)
| | - Stephen Wagner
- Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Atul Chugh
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Kenneth S Ramos
- Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY (K.S.R., A.B.)
| | - Sanjay Srivastava
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Deirdre Higdon
- Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - David J Tollerud
- Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville, KY (N.D.J., D.J.T., R.Y.)
| | - Andrew DeFilippis
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.) Department of Medicine, Johns Hopkins University, Baltimore, MD (A.D.F.)
| | - Carrie Becher
- Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Brad Wyatt
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - James McCracken
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Wes Abplanalp
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Shesh N Rai
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Department of Bioinformatics and Biostatics, University of Louisville, Louisville, KY (S.N.R.) Biostatistics Shared Facility, JG Brown Cancer Center, University of Louisville, Louisville, KY (S.N.R.)
| | - Tiffany Ciszewski
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Zhengzhi Xie
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
| | - Ray Yeager
- Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville, KY (N.D.J., D.J.T., R.Y.)
| | - Sumanth D Prabhu
- Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.) Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL (S.D.P.)
| | - Aruni Bhatnagar
- Diabetes and Obesity Center, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., A.C., S.S., A.D.F., B.W., J.M.C., W.A., S.N.R., T.C., Z.X., A.B.) Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY (K.S.R., A.B.) Institue of Molecular Cardiology, University of Louisville, Louisville, KY (N.D.J., D.J.C., D.W.R., T.E.T., S.W., A.C., S.S., D.H., A.D.F., C.B., B.W., J.M.C., W.A., T.C., Z.X., S.D.P., A.B.)
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Oxidation-induced loss of the ability of HDL to counteract the inhibitory effect of oxidized LDL on vasorelaxation. Heart Vessels 2014; 30:845-9. [PMID: 25031153 DOI: 10.1007/s00380-014-0543-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 06/27/2014] [Indexed: 02/02/2023]
Abstract
Several current diseases are associated with an increase in the oxidation of HDL, which is likely to impair their functionality. Our aim was to identify whether oxidation could change the protective effect of HDL against the deleterious effect on vasoreactivity induced by oxidative stress. HDL from healthy subjects were oxidized in vitro by Cu(2+), and the ability of oxidized HDL to counteract the inhibitory effect of oxidized LDL on acetylcholine-induced vasodilation was tested on isolated rabbit aorta rings. Oxidation of HDL was evidenced by the increase in the 7-oxysterols/cholesterol ratio (3.20 ± 1.12 vs 0.02 ± 0.01 % in native HDL, p < 0.05). Oxidized LDL inhibited endothelium-dependent vasodilation (E max = 50.2 ± 5.0 vs 92.5 ± 1.7 % for incubation in Kreb's buffer, p < 0.05) and native HDL counteracted this inhibition (E max = 72.4 ± 4.8 vs 50.2 ± 5.0 % p < 0.05). At the opposite, oxidized HDL had no effect on oxidized LDL-induced inhibition on endothelium-dependent vasorelaxation (E max = 53.7 ± 4.8 vs 50.2 ± 5.0 %, NS). HDL oxidation is associated with a decreased ability of HDL to remove 7-oxysterols from oxidized LDL. In conclusion, these results show that oxidation of HDL induces the loss of their protective effect against endothelial dysfunction, which could promote atherosclerosis in diseases associated with increased oxidative stress.
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O'Toole TE, Abplanalp W, Li X, Cooper N, Conklin DJ, Haberzettl P, Bhatnagar A. Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a. Toxicol Sci 2014; 140:271-82. [PMID: 24812010 DOI: 10.1093/toxsci/kfu087] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Acrolein is a major reactive component of vehicle exhaust, and cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation, and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high-throughput technology, we found that treatment of cultured human umbilical vein endothelial cells with acrolein led to a significant (>1.5-fold) upregulation of 12, and downregulation of 15, miRNAs. Among the miRNAs upregulated were members of the let-7 family and this upregulation was associated with decreased expression of their protein targets, β3 integrin, Cdc34, and K-Ras. Exposure to acrolein attenuated β3 integrin-dependent migration and reduced Akt phosphorylation in response to insulin. These effects of acrolein on endothelial cell migration and insulin signaling were reversed by expression of a let-7a inhibitor. Also, inhalation exposure of mice to acrolein (1 ppm x 6 h/day x 4 days) upregulated let-7a and led to a decrease in insulin-stimulated Akt phosphorylation in the aorta. These results suggest that acrolein exposure has broad effects on endothelial miRNA repertoire and that attenuation of endothelial cell migration and insulin signaling by acrolein is mediated in part by the upregulation of let-7a. This mechanism may be a significant feature of vascular injury caused by inflammation, oxidized lipids, and exposure to environmental pollutants.
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Affiliation(s)
| | | | - Xiaohong Li
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40202
| | - Nigel Cooper
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, Kentucky 40202
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Tran TN, Kosaraju MG, Tamamizu-Kato S, Akintunde O, Zheng Y, Bielicki JK, Pinkerton K, Uchida K, Lee YY, Narayanaswami V. Acrolein modification impairs key functional features of rat apolipoprotein E: identification of modified sites by mass spectrometry. Biochemistry 2014; 53:361-75. [PMID: 24325674 DOI: 10.1021/bi401404u] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Apolipoprotein E (apoE), an antiatherogenic apolipoprotein, plays a significant role in the metabolism of lipoproteins. It lowers plasma lipid levels by acting as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins, in addition to playing a role in promoting macrophage cholesterol efflux in atherosclerotic lesions. The objective of this study is to examine the effect of acrolein modification on the structure and function of rat apoE and to determine the sites and nature of modification by mass spectrometry. Acrolein is a highly reactive aldehyde, which is generated endogenously as one of the products of lipid peroxidation and is present in the environment in pollutants such as tobacco smoke and heated oils. In initial studies, acrolein-modified apoE was identified by immunoprecipitation using an acrolein-lysine specific antibody in the plasma of 10-week old male rats that were exposed to filtered air (FA) or low doses of environmental tobacco smoke (ETS). While both groups displayed acrolein-modified apoE in the lipoprotein fraction, the ETS group had higher levels in the lipid-free fraction compared with the FA group. This observation provided the rationale to further investigate the effect of acrolein modification on rat apoE at a molecular level. Treatment of recombinant rat apoE with a 10-fold molar excess of acrolein resulted in (i) a significant decrease in lipid-binding and cholesterol efflux abilities, (ii) impairment in the LDLr- and heparin-binding capabilities, and (iii) significant alterations in the overall stability of the protein. The disruption in the functional abilities is attributed directly or indirectly to acrolein modification yielding an aldimine adduct at K149 and K155 (+38); a propanal adduct at K135 and K138 (+56); an N(ε)-(3-methylpyridinium)lysine (MP-lysine) at K64, K67, and K254 (+76), and an N(ε)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) derivative at position K68 (+94), as determined by matrix-assisted laser desorption/ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). The loss of function may also be attributed to alterations in the overall fold of the protein as noted by changes in the guanidine HCl-induced unfolding pattern and to protein cross-linking. Overall, disruption of the structural and functional integrity of apoE by oxidative modification of essential lysine residues by acrolein is expected to affect its role in maintaining plasma cholesterol homeostasis and lead to dysregulation in lipid metabolism.
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Affiliation(s)
- Tuyen N Tran
- Department of Chemistry & Biochemistry, California State University Long Beach , Long Beach, California 90840, United States
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Tsutsui A, Imamaki R, Kitazume S, Hanashima S, Yamaguchi Y, Kaneda M, Oishi S, Fujii N, Kurbangalieva A, Taniguchi N, Tanaka K. Polyamine modification by acrolein exclusively produces 1,5-diazacyclooctanes: a previously unrecognized mechanism for acrolein-mediated oxidative stress. Org Biomol Chem 2014; 12:5151-7. [DOI: 10.1039/c4ob00761a] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Polyamines were found to react with acrolein to produce 1,5-diazacyclooctane.
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Affiliation(s)
- Ayumi Tsutsui
- Biofunctional Synthetic Chemistry Laboratory
- RIKEN
- Saitama 351-0198, Japan
| | - Rie Imamaki
- Systems Glycobiology Research Group
- RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
- RIKEN Global Research Cluster
- RIKEN
- Saitama 351-0198, Japan
| | - Shinobu Kitazume
- Systems Glycobiology Research Group
- RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
- RIKEN Global Research Cluster
- RIKEN
- Saitama 351-0198, Japan
| | - Shinya Hanashima
- Systems Glycobiology Research Group
- RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
- RIKEN Global Research Cluster
- RIKEN
- Saitama 351-0198, Japan
| | - Yoshiki Yamaguchi
- Systems Glycobiology Research Group
- RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
- RIKEN Global Research Cluster
- RIKEN
- Saitama 351-0198, Japan
| | - Masato Kaneda
- Graduate School of Pharmaceutical Sciences
- Kyoto University
- Kyoto 606-8501, Japan
| | - Shinya Oishi
- Graduate School of Pharmaceutical Sciences
- Kyoto University
- Kyoto 606-8501, Japan
| | - Nobutaka Fujii
- Graduate School of Pharmaceutical Sciences
- Kyoto University
- Kyoto 606-8501, Japan
| | - Almira Kurbangalieva
- Biofunctional Chemistry Laboratory
- A. Butlerov Institute of Chemistry
- Kazan Federal University
- Kazan 420008, Russia
| | - Naoyuki Taniguchi
- Systems Glycobiology Research Group
- RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
- RIKEN Global Research Cluster
- RIKEN
- Saitama 351-0198, Japan
| | - Katsunori Tanaka
- Biofunctional Synthetic Chemistry Laboratory
- RIKEN
- Saitama 351-0198, Japan
- Biofunctional Chemistry Laboratory
- A. Butlerov Institute of Chemistry
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47
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Leman LJ, Maryanoff BE, Ghadiri MR. Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem 2013; 57:2169-96. [PMID: 24168751 DOI: 10.1021/jm4005847] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Certain amphipathic α-helical peptides can functionally mimic many of the properties of full-length apolipoproteins, thereby offering an approach to modulate high-density lipoprotein (HDL) for combating atherosclerosis. In this Perspective, we summarize the key findings and advances over the past 25 years in the development of peptides that mimic apolipoproteins, especially apolipoprotein A-I (apoA-I). This assemblage of information provides a reasonably clear picture of the state of the art in the apolipoprotein mimetic field, an appreciation of the potential for such agents in pharmacotherapy, and a sense of the opportunities for optimizing the functional properties of HDL.
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Affiliation(s)
- Luke J Leman
- Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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Colzani M, Aldini G, Carini M. Mass spectrometric approaches for the identification and quantification of reactive carbonyl species protein adducts. J Proteomics 2013; 92:28-50. [DOI: 10.1016/j.jprot.2013.03.030] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 03/26/2013] [Accepted: 03/27/2013] [Indexed: 01/28/2023]
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49
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Borja MS, Zhao L, Hammerson B, Tang C, Yang R, Carson N, Fernando G, Liu X, Budamagunta MS, Genest J, Shearer GC, Duclos F, Oda MN. HDL-apoA-I exchange: rapid detection and association with atherosclerosis. PLoS One 2013; 8:e71541. [PMID: 24015188 PMCID: PMC3756009 DOI: 10.1371/journal.pone.0071541] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 06/28/2013] [Indexed: 01/23/2023] Open
Abstract
High density lipoprotein (HDL) cholesterol levels are associated with decreased risk of cardiovascular disease, but not all HDL are functionally equivalent. A primary determinant of HDL functional status is the conformational adaptability of its main protein component, apoA-I, an exchangeable apolipoprotein. Chemical modification of apoA-I, as may occur under conditions of inflammation or diabetes, can severely impair HDL function and is associated with the presence of cardiovascular disease. Chemical modification of apoA-I also impairs its ability to exchange on and off HDL, a critical process in reverse cholesterol transport. In this study, we developed a method using electron paramagnetic resonance spectroscopy (EPR) to quantify HDL-apoA-I exchange. Using this approach, we measured the degree of HDL-apoA-I exchange for HDL isolated from rabbits fed a high fat, high cholesterol diet, as well as human subjects with acute coronary syndrome and metabolic syndrome. We observed that HDL-apoA-I exchange was markedly reduced when atherosclerosis was present, or when the subject carries at least one risk factor of cardiovascular disease. These results show that HDL-apoA-I exchange is a clinically relevant measure of HDL function pertinent to cardiovascular disease.
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Affiliation(s)
- Mark S. Borja
- Children's Hospital Oakland Research Institute, Oakland, California, United States of America
| | - Lei Zhao
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Bradley Hammerson
- Accent Assays, Inc., Sacramento, California, United States of America
| | - Chongren Tang
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Richard Yang
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Nancy Carson
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Gayani Fernando
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Xiaoqin Liu
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Madhu S. Budamagunta
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America
| | - Jacques Genest
- Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Gregory C. Shearer
- Cardiovascular Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America
- Department of Internal Medicine and Department of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, United States of America
| | - Franck Duclos
- Cardiovascular Drug Discovery, Bristol-Myers Squibb Company, Pennington, New Jersey, United States of America
| | - Michael N. Oda
- Children's Hospital Oakland Research Institute, Oakland, California, United States of America
- * E-mail:
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50
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Bachi A, Dalle-Donne I, Scaloni A. Redox Proteomics: Chemical Principles, Methodological Approaches and Biological/Biomedical Promises. Chem Rev 2012. [DOI: 10.1021/cr300073p] [Citation(s) in RCA: 189] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Angela Bachi
- Biological Mass Spectrometry Unit, San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Andrea Scaloni
- Proteomics & Mass Spectrometry Laboratory, ISPAAM, National Research Council, 80147 Naples, Italy
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