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Tian W, Ju J, Guan B, Wang T, Zhang J, Song L, Xu H. Role of hyperhomocysteinemia in atherosclerosis: from bench to bedside. Ann Med 2025; 57:2457527. [PMID: 39898976 PMCID: PMC11792134 DOI: 10.1080/07853890.2025.2457527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 01/07/2025] [Accepted: 01/08/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Atherosclerosis is a leading cause of global mortality, driven by complex interactions between genetic, metabolic, and environmental factors. Among these, hyperhomocysteinemia (HHcy) has emerged as a significant and modifiable risk factor, contributing to endothelial dysfunction, oxidative stress, and vascular inflammation. Despite increasing recognition of its role in atherogenesis, the precise mechanisms and clinical implications of HHcy remain incompletely understood, necessitating a comprehensive review to connect recent mechanistic insights with practical applications. METHODS We analyzed the various mechanisms whereby HHcy accelerates the progression of atherosclerosis, and conducted a comprehensive review of publications in the fields of HHcy and atherosclerosis. RESULTS HHcy promotes atherosclerosis through several mechanisms, including inflammation, oxidative stress, epigenetic modification, and lipoprotein metabolism alteration. Moreover, this discussion extends to current strategies for the prevention and clinical management of HHcy-induced atherosclerosis. CONCLUSION This review consolidates and elucidates the latest advancements and insights into the role of HHcy in atherosclerosis. The comprehensive narrative connects fundamental research with clinical applications. Contemporary studies highlight the complex interplay between HHcy and atherosclerosis, establishing HHcy as not only a contributing risk factor but also an accelerator of various atherogenic processes.
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Affiliation(s)
- Wende Tian
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing China
| | - Jianqing Ju
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
| | - Baoyi Guan
- Department of Internal Medicine-Cardiovascular, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tongxin Wang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, China Academy of Chinese Medical Sciences, Beijing China
| | - Jiqian Zhang
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Luxia Song
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
| | - Hao Xu
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing China
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Giurranna E, Nencini F, Borghi S, Barbaro I, Taddei N, Fiorillo C, Becatti M. Homocysteinylation of Fibrinogen: A Post-Translational Link to Thrombosis. Int J Mol Sci 2025; 26:5471. [PMID: 40564934 DOI: 10.3390/ijms26125471] [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] [Received: 05/08/2025] [Revised: 06/04/2025] [Accepted: 06/05/2025] [Indexed: 06/28/2025] Open
Abstract
Homocysteinylation, a post-translational modification involving the covalent attachment of homocysteine to proteins, has emerged as a critical mechanism linking hyperhomocysteinemia to thrombotic disease. This review focuses on the homocysteinylation of fibrinogen, a key coagulation factor, and its impact on clot structure and function. Evidence indicates that elevated homocysteine levels can induce significant changes in fibrin architecture, promoting the formation of dense, rigid clots with reduced permeability and impaired fibrinolytic susceptibility, thus fostering a prothrombotic environment. However, inconsistencies in reported effects on fiber diameter and polymerization kinetics highlight the need for standardized experimental protocols. Advances in proteomics and high-resolution imaging are expected to clarify the molecular underpinnings of these modifications. Moreover, homocysteinylation intersects with oxidative stress and may serve as a mechanistic bridge between metabolic and vascular dysfunction. Understanding its role not only enhances insight into thrombosis but also opens avenues for biomarker discovery and targeted therapies in cardiovascular and potentially neurological disorders.
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Affiliation(s)
- Elvira Giurranna
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Francesca Nencini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Serena Borghi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Ilenia Barbaro
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, 50134 Firenze, Italy
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Xu L, Wang Y, Wang Y, Wang L, Du P, Cheng J, Zhang C, Jiao T, Xing L, Tapu MSR, Jia H, Li J. Early Use of PCSK9 Inhibitors in the Prognosis of Patients with Acute Coronary Syndrome by Protecting Vascular Endothelial Function. Pharmacology 2024; 110:1-14. [PMID: 38964284 DOI: 10.1159/000540083] [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] [Received: 03/21/2024] [Accepted: 06/26/2024] [Indexed: 07/06/2024]
Abstract
INTRODUCTION Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function. METHODS A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments. RESULTS After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs. CONCLUSION PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.
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Affiliation(s)
- Linghao Xu
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuanqi Wang
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yiqiong Wang
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Liang Wang
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Peizhao Du
- Department of Cardiology, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Cheng
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chunsheng Zhang
- Department of Cardiology, East Hospital of Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Tiantian Jiao
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lijian Xing
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Md Sakibur Rahman Tapu
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haonan Jia
- Laboratory of Molecular Neural Biology, School of Life Sciences and Institute of Systems Biology, Shanghai University, Shanghai, China
| | - Jiming Li
- Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
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Alp A, Saruhan E, Doğan E, Genek DG, Huddam B. Time to Change Our Viewpoints to Assess Renal Risks in Patients with Solitary Kidneys beyond Traditional Approaches? J Clin Med 2023; 12:6885. [PMID: 37959350 PMCID: PMC10649944 DOI: 10.3390/jcm12216885] [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: 09/22/2023] [Revised: 10/26/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Solitary functioning kidney (SFK) can be defined as the absence or hypofunction of a kidney due to acquired or congenital reasons. A congenital solitary functioning kidney (cSFK) is more common than is an acquired one (aSFK) and is characterized by the anatomical absence (agenesis) or hypofunction (hypoplasia; hypodysplasia) of one kidney from birth. Among the acquired causes, the most important is nephrectomy (Nx) (due to the donor, trauma or mass resection). Patients with SFK are at risk for the development of chronic kidney disease (CKD) in the long term. This risk potential is also significantly affected by hypertension. The relationship between hypertension and subclinical chronic inflammation is a connection that has not yet been fully clarified pathogenetically, but there are many studies highlighting this association. In recent years, studies examining different fibrosis and inflammation biomarkers in terms of the evaluation and prediction of renal risks have become increasingly popular in the literature. Oxidative stress is known to play an important role in homocysteine-induced endothelial dysfunction and has been associated with hypertension. In our study, we aimed to investigate the relationship between ambulatory blood pressure monitoring (ABPM) and urinary/serum fibrosis and inflammatory markers in patients with SFK. We prospectively investigated the relationship between ABPM results and soluble urokinase plasminogen activator receptor (suPAR), procollagen type III N-terminal peptide (PIIINP), homocysteine and other variables in 85 patients with SFK and compared them between cSFK and aSFK groups. In the etiology of SFK, a congenital or acquired origin may differ in terms of the significance of biomarkers. In particular, the serum homocysteine level may be associated with different clinical outcomes in patients with cSFK and aSFK.
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Affiliation(s)
- Alper Alp
- Department of Nephrology, Faculty of Medicine, Mugla Sıtkı Koçman University, 48000 Mugla, Turkey; (D.G.G.); (B.H.)
| | - Ercan Saruhan
- Department of Medical Biochemistry, Faculty of Medicine, Mugla Sıtkı Koçman University, 48000 Mugla, Turkey;
| | - Emrah Doğan
- Department of Radiology, Faculty of Medicine, Mugla Sıtkı Koçman University, 48000 Mugla, Turkey;
| | - Dilek Gibyeli Genek
- Department of Nephrology, Faculty of Medicine, Mugla Sıtkı Koçman University, 48000 Mugla, Turkey; (D.G.G.); (B.H.)
| | - Bülent Huddam
- Department of Nephrology, Faculty of Medicine, Mugla Sıtkı Koçman University, 48000 Mugla, Turkey; (D.G.G.); (B.H.)
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Yalameha B, Reza Nejabati H. Urinary Exosomal Metabolites: Overlooked Clue for Predicting Cardiovascular Risk. Clin Chim Acta 2023:117445. [PMID: 37315726 DOI: 10.1016/j.cca.2023.117445] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/10/2023] [Accepted: 06/11/2023] [Indexed: 06/16/2023]
Abstract
Over the last decade, increasing research has focused on urinary exosomes (UEs) in biological fluids and their relationship with physiological and pathological processes. UEs are membranous vesicles with a size of 40-100 nm, containing a number of bioactive molecules such as proteins, lipids, mRNAs, and miRNAs. These vesicles are an inexpensive non-invasive source that can be used in clinical settings to differentiate healthy patients from diseased patients, thereby serving as potential biomarkers for the early identification of disease. Recent studies have reported the isolation of small molecules called exosomal metabolites from individuals' urine with different diseases. These metabolites could utilize for a variety of purposes, such as the discovery of biomarkers, investigation of mechanisms related to disease development, and importantly prediction of cardiovascular diseases (CVDs) risk factors, including thrombosis, inflammation, oxidative stress, hyperlipidemia as well as homocysteine. It has been indicated that alteration in urinary metabolites of N1-methylnicotinamide, 4-aminohippuric acid, and citric acid can be valuable in predicting cardiovascular risk factors, providing a novel approach to evaluating the pathological status of CVDs. Since the UEs metabolome has been clearly and precisely so far unexplored in CVDs, the present study has specifically addressed the role of the mentioned metabolites in the prediction of CVDs risk factors.
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Affiliation(s)
- Banafsheh Yalameha
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamid Reza Nejabati
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Yuan D, Chu J, Lin H, Zhu G, Qian J, Yu Y, Yao T, Ping F, Chen F, Liu X. Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis. Front Cardiovasc Med 2023; 9:1109445. [PMID: 36727029 PMCID: PMC9884709 DOI: 10.3389/fcvm.2022.1109445] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
Homocysteine (Hcy) is an intermediate amino acid formed during the conversion from methionine to cysteine. When the fasting plasma Hcy level is higher than 15 μmol/L, it is considered as hyperhomocysteinemia (HHcy). The vascular endothelium is an important barrier to vascular homeostasis, and its impairment is the initiation of atherosclerosis (AS). HHcy is an important risk factor for AS, which can promote the development of AS and the occurrence of cardiovascular events, and Hcy damage to the endothelium is considered to play a very important role. However, the mechanism by which Hcy damages the endothelium is still not fully understood. This review summarizes the mechanism of Hcy-induced endothelial injury and the treatment methods to alleviate the Hcy induced endothelial dysfunction, in order to provide new thoughts for the diagnosis and treatment of Hcy-induced endothelial injury and subsequent AS-related diseases.
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Shcheblykin DV, Bolgov AA, Pokrovskii MV, Stepenko JV, Tsuverkalova JM, Shcheblykina OV, Golubinskaya PA, Korokina LV. Endothelial dysfunction: developmental mechanisms and therapeutic strategies. RESEARCH RESULTS IN PHARMACOLOGY 2022. [DOI: 10.3897/rrpharmacology.8.80376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Introduction: Every year the importance of the normal functioning of the endothelial layer of the vascular wall in maintaining the health of the body becomes more and more obvious.
The physiological role of the endothelium: The endothelium is a metabolically active organ actively involved in the regulation of hemostasis, modulation of inflammation, maintenance of hemovascular homeostasis, regulation of angiogenesis, vascular tone, and permeability.
Risk factors for the development of endothelial dysfunction: Currently, insufficient bioavailability of nitric oxide is considered the most significant risk factor for endothelial dysfunction.
Mechanisms of development of endothelial dysfunction: The genesis of endothelial dysfunction is a multifactorial process. Among various complex mechanisms, this review examines oxidative stress, inflammation, hyperglycemia, vitamin D deficiency, dyslipidemia, excess visceral fat, hyperhomocysteinemia, hyperuricemia, as well as primary genetic defect of endotheliocytes, as the most common causes in the population underlying the development of endothelial dysfunction.
Markers of endothelial dysfunction in various diseases: This article discusses the main biomarkers of endothelial dysfunction currently used, as well as promising biomarkers in the future for laboratory diagnosis of this pathology.
Therapeutic strategies: Therapeutic approaches to the endothelium in order to prevent or reduce a degree of damage to the vascular wall are briefly described.
Conclusion: Endothelial dysfunction is a typical pathological process involved in the pathogenesis of many diseases. Thus, pharmacological agents with endothelioprotective properties can provide more therapeutic benefits than a drug without such an effect.
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COVID-19 and One-Carbon Metabolism. Int J Mol Sci 2022; 23:ijms23084181. [PMID: 35456998 PMCID: PMC9026976 DOI: 10.3390/ijms23084181] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 12/31/2022] Open
Abstract
Dysregulation of one-carbon metabolism affects a wide range of biological processes and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Accumulating evidence suggests that one-carbon metabolism plays an important role in COVID-19. The symptoms of long COVID-19 are similar to those presented by subjects suffering from vitamin B12 deficiency (pernicious anemia). The metabolism of a cell infected by the SARS-CoV-2 virus is reshaped to fulfill the need for massive viral RNA synthesis, which requires de novo purine biosynthesis involving folate and one-carbon metabolism. Many aspects of host sulfur amino acid metabolism, particularly glutathione metabolism underlying antioxidant defenses, are also taken over by the SARS-CoV-2 virus. The purpose of this review is to summarize recent findings related to one-carbon metabolism and sulfur metabolites in COVID-19 and discuss how they inform strategies to combat the disease.
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9
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Further comment on articles pertaining to: "Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19". Med Hypotheses 2021; 155:110676. [PMID: 34555782 PMCID: PMC8418050 DOI: 10.1016/j.mehy.2021.110676] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/09/2021] [Accepted: 09/01/2021] [Indexed: 11/24/2022]
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Carnagarin R, Nolde JM, Ward NC, Lugo-Gavidia LM, Chan J, Robinson S, Jose A, Joyson A, Azzam O, Galindo Kiuchi M, Mwipatayi BP, Schlaich MP. Homocysteine predicts vascular target organ damage in hypertension and may serve as guidance for first-line antihypertensive therapy. J Clin Hypertens (Greenwich) 2021; 23:1380-1389. [PMID: 34137162 PMCID: PMC8678735 DOI: 10.1111/jch.14265] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/22/2021] [Accepted: 04/24/2021] [Indexed: 12/27/2022]
Abstract
Homocysteine is an independent risk factor for cardiovascular and cerebrovascular disease and has been proposed to contribute to vascular dysfunction. We sought to determine in a real-world clinical setting whether homocysteine levels were associated with hypertension mediated organ damage (HMOD) and could guide treatment choices in hypertension. We performed a cross-sectional analysis of prospectively collected data in 145 hypertensive patients referred to our tertiary hypertension clinic at Royal Perth Hospital and analyzed the association of homocysteine with HMOD, renin-angiotensin-aldosterone system (RAAS), and RAAS blockade. The average age of participants was 56 ± 17 years, and there was a greater proportion of males than females (89 vs. 56). Regression analysis showed that homocysteine was significantly associated with PWV (β = 1.99; 95% CI 0.99-3.0; p < .001), albumin-creatinine ratio (lnACR: β = 1.14; 95% CI 0.47, 1.8; p < .001), 24 h urinary protein excretion (β = 0.7; 95% CI 0.48, 0.92; p < .001), and estimated glomerular filtration rate (β = -29.4; 95% CI -36.35, -22.4; p < .001), which persisted after adjusting for potential confounders such as age, sex, 24 h BP, inflammation, smoking, diabetes mellitus (DM), and dyslipidemia. A positive predictive relationship was observed between plasma homocysteine levels and PWV, with every 1.0 µmol/L increase in homocysteine associated with a 0.1 m/s increase in PWV. Homocysteine was significantly associated with elevated aldosterone concentration (β = 0.26; p < .001), and with attenuation of ACEi mediated systolic BP lowering and regression of HMOD compared to angiotensin receptor blockers in higher physiological ranges of homocysteine. Our results indicate that homocysteine is associated with hypertension mediated vascular damage and could potentially serve to guide first-line antihypertensive therapy.
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Affiliation(s)
- Revathy Carnagarin
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Janis M Nolde
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Natalie C Ward
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Leslie Marisol Lugo-Gavidia
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Justine Chan
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Sandi Robinson
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Ancy Jose
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Anu Joyson
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Omar Azzam
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Márcio Galindo Kiuchi
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia
| | - Bibombe P Mwipatayi
- Department of Vascular Surgery, Royal Perth Hospital, Perth, WA, Australia.,Faculty of Medicine, School of Surgery, Dentistry and Health Sciences, University of Western Australia, Perth, WA, Australia
| | - Markus P Schlaich
- Faculty of Medicine, Dentistry & Health Sciences, School of Medicine - Royal Perth Hospital Unit, Dobney Hypertension Centre, Royal Perth Hospital Research Foundation, The University of Western Australia, Perth, WA, Australia.,Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, WA, Australia.,Neurovascular Hypertension & Kidney Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Vic., Australia
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Nardin M, Verdoia M, Gioscia R, Negro F, De Luca G. Impact of renin angiotensin system inhibitors on homocysteine levels and platelets reactivity in patients on dual antiplatelet therapy. Nutr Metab Cardiovasc Dis 2021; 31:1276-1285. [PMID: 33549433 DOI: 10.1016/j.numecd.2020.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 10/03/2020] [Accepted: 12/03/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND AIMS Dual antiplatelet therapy (DAPT) and Renin-angiotensin system inhibitors (RASi) represent the cornerstone in the treatment of patients undergoing percutaneous coronary interventions (PCI), mainly after an acute ischemic event. However, high-on treatment residual platelet reactivity (HRPR), is not infrequent despite optimal medical treatment. Homocysteine (Hcy) is a metabolite of methionine catabolism linked to atherothrombosis. Recently, a potential crosstalk between RAS and Hcy has been suggested, potentially favouring platelet aggregation and cardiovascular disease.Therefore, we aimed to investigate the impact of RASi on Hcy levels and platelet aggregation in patients on DAPT after PCI. METHODS AND RESULTS Patients undergoing PCI on DAPT with ASA plus an ADP-antagonist (clopidogrel, ticagrelor or prasugrel), were included. RASi comprised angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). Aggregation tests were performed by Multiple Electrode Aggregometry. We included 1210 patients, of whom 862 (71.2%) were on treatment with RASi. Overall, DAPT composition was ASA+clopidogrel in 566 (46.8%) patients, ASA+ticagrelor in 428 (35.4%) and ASA+prasugrel in 216 (17.9%). Median values of Hcy were higher in RASi patients (p = 0.006), who displayed a higher percentage of Hcy above the median value (52.4% vs. 44.8%, p = 0.019, adjustedOR [95%CI] = 1.40 [1.04-1.88], p = 0.027). No differences in HRPR rate were found according to RASi use for ASPI test (3.6% vs. 3.3%, p = 0.88) and ADP test (25.6% vs. 24.3%,p = 0.62; adjustedOR [95%CI] = 1.23 [0.89-1.70], p = 0.220) and according to ADP-antagonist type. A direct linear relationship was observed between platelet reactivity and Hcy in both patients receiving RASi and untreated ones, with higher values of platelet aggregation being observed in patients with Hcy above the median, independently from RASi administration and DAPT strategy. CONCLUSION In patients on DAPT after PCI, RASi treatment did not emerge as an independent predictor of HRPR. However, the levels of Hcy were significantly elevated in patients on RASi and related to higher values of platelet reactivity, independently from the DAPT strategy.
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Affiliation(s)
- Matteo Nardin
- Division of Cardiology, Azienda Ospedaliera-Universitaria "Maggiore della Carità", Eastern Piedmont University, Novara, Italy; Department of Medicine, ASST "Spedali Civili", University of Brescia, Brescia, Italy
| | - Monica Verdoia
- Division of Cardiology, Azienda Ospedaliera-Universitaria "Maggiore della Carità", Eastern Piedmont University, Novara, Italy; Division of Cardiology, "Ospedale degli Infermi", Biella, Italy
| | - Rocco Gioscia
- Division of Cardiology, Azienda Ospedaliera-Universitaria "Maggiore della Carità", Eastern Piedmont University, Novara, Italy
| | - Federica Negro
- Division of Cardiology, Azienda Ospedaliera-Universitaria "Maggiore della Carità", Eastern Piedmont University, Novara, Italy
| | - Giuseppe De Luca
- Division of Cardiology, Azienda Ospedaliera-Universitaria "Maggiore della Carità", Eastern Piedmont University, Novara, Italy.
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Bok R, Guerra DD, Lorca RA, Wennersten SA, Harris PS, Rauniyar AK, Stabler SP, MacLean KN, Roede JR, Brown LD, Hurt KJ. Cystathionine γ-lyase promotes estrogen-stimulated uterine artery blood flow via glutathione homeostasis. Redox Biol 2020; 40:101827. [PMID: 33485059 PMCID: PMC7823052 DOI: 10.1016/j.redox.2020.101827] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/16/2020] [Accepted: 12/01/2020] [Indexed: 12/16/2022] Open
Abstract
During pregnancy, estrogen (E2) stimulates uterine artery blood flow (UBF) by enhancing nitric oxide (NO)-dependent vasodilation. Cystathionine γ-lyase (CSE) promotes vascular NO signaling by producing hydrogen sulfide (H2S) and by maintaining the ratio of reduced-to-oxidized intracellular glutathione (GSH/GSSG) through l-cysteine production. Because redox homeostasis can influence NO signaling, we hypothesized that CSE mediates E2 stimulation of UBF by modulating local intracellular cysteine metabolism and GSH/GSSG levels to promote redox homeostasis. Using non-pregnant ovariectomized WT and CSE-null (CSE KO) mice, we performed micro-ultrasound of mouse uterine and renal arteries to assess changes in blood flow upon exogenous E2 stimulation. We quantified serum and uterine artery NO metabolites (NOx), serum amino acids, and uterine and renal artery GSH/GSSG. WT and CSE KO mice exhibited similar baseline uterine and renal blood flow. Unlike WT, CSE KO mice did not exhibit expected E2 stimulation of UBF. Renal blood flow was E2-insensitive for both genotypes. While serum and uterine artery NOx were similar between genotypes at baseline, E2 decreased NOx in CSE KO serum. Cysteine was also lower in CSE KO serum, while citrulline and homocysteine levels were elevated. E2 and CSE deletion additively decreased GSH/GSSG in uterine arteries. In contrast, renal artery GSH/GSSG was insensitive to E2 or CSE deletion. Together, these findings suggest that CSE maintenance of uterine artery GSH/GSSG facilitates nitrergic signaling in uterine arteries and is required for normal E2 stimulation of UBF. These data have implications for pregnancy pathophysiology and the selective hormone responses of specific vascular beds.
CSE-null mice exhibit abnormal estrogen augmentation of uterine artery blood flow. Estrogen lowers uterine artery nitric oxide metabolites in CSE null mice. CSE loss and estrogen additively impair uterine artery glutathione homeostasis. Neither CSE loss nor estrogen influences renal artery blood flow or glutathione.
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Affiliation(s)
- Rachael Bok
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
| | - Damian D Guerra
- Department of Biology, University of Louisville, 2301 S. 3rd Street, Louisville, KY, 40292, USA
| | - Ramón A Lorca
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
| | - Sara A Wennersten
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
| | - Peter S Harris
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
| | - Abhishek K Rauniyar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
| | - Sally P Stabler
- Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
| | - Kenneth N MacLean
- Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
| | - James R Roede
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
| | - Laura D Brown
- Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Perinatal Research Center, 13243 E. 23rd Avenue, Aurora, CO, 80045, USA
| | - K Joseph Hurt
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA.
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13
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Zhao W, Cheng H, Zhu Y. A compound reflects the level of homocysteine based on Rhodamine B and its ability to respond to homocysteine in the plasma of diabetic patients. J Clin Lab Anal 2020; 34:e23202. [PMID: 31995653 PMCID: PMC7246376 DOI: 10.1002/jcla.23202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/10/2019] [Accepted: 12/16/2019] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The level of homocysteine (Hcy) is significantly elevated in the plasma of patients with diabetes. The increased plasma Hcy level is positively correlated with the severity of the disease and is one of the important causes of diabetic complications. METHODS We designed and synthesized a compound could reflect the level of Hcy based on rhodamine B, and the structure was verified by 1H-NMR and EI-HRMS. Then, the linearity, repeatability, selectivity, and cellar toxicity, the effects of the fluid viscosity and pH of compound on Hcy were measured; meanwhile, the response of Hcy level in the plasma of diabetic patients was detected. RESULTS This is a novel compound that has never been reported. The compound showed a satisfactory linear range and repeatability at the viscosity and pH of physiological fluid. In addition, the compound was capable of evading the interference from other amino acids and metal ions, and it exhibited high selectivity toward Hcy. CONCLUSION The compound showed increased responsiveness to plasma Hcy in patients with diabetes in comparison with healthy individuals and effectively reflected plasma Hcy levels in healthy individuals and diabetic patients. Therefore, the compound is expected to be used in the diagnosis of diabetes mellitus.
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Affiliation(s)
| | - Han Cheng
- Department of Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin, China
| | - Yu Zhu
- Department of Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin, China
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14
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Jakubowski H. Homocysteine Modification in Protein Structure/Function and Human Disease. Physiol Rev 2019; 99:555-604. [PMID: 30427275 DOI: 10.1152/physrev.00003.2018] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B12, and one carbon metabolism, is associated with poor health, including heart and brain diseases. Earlier studies show that patients with severe hyperhomocysteinemia, first identified in the 1960s, exhibit neurological and cardiovascular abnormalities and premature death due to vascular complications. Although homocysteine is considered to be a nonprotein amino acid, studies over the past 2 decades have led to discoveries of protein-related homocysteine metabolism and mechanisms by which homocysteine can become a component of proteins. Homocysteine-containing proteins lose their biological function and acquire cytotoxic, proinflammatory, proatherothrombotic, and proneuropathic properties, which can account for the various disease phenotypes associated with hyperhomocysteinemia. This review describes mechanisms by which hyperhomocysteinemia affects cellular proteostasis, provides a comprehensive account of the biological chemistry of homocysteine-containing proteins, and discusses pathophysiological consequences and clinical implications of their formation.
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Affiliation(s)
- Hieronim Jakubowski
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers-New Jersey Medical School, International Center for Public Health , Newark, New Jersey ; and Department of Biochemistry and Biotechnology, Poznań University of Life Sciences , Poznań , Poland
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15
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Djuric D, Jakovljevic V, Zivkovic V, Srejovic I. Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol 2018; 96:991-1003. [PMID: 30130426 DOI: 10.1139/cjpp-2018-0112] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Homocysteine, an amino acid containing a sulfhydryl group, is an intermediate product during metabolism of the amino acids methionine and cysteine. Hyperhomocysteinemia is used as a predictive risk factor for cardiovascular disorders, the stroke progression, screening for inborn errors of methionine metabolism, and as a supplementary test for vitamin B12 deficiency. Two organic systems in which homocysteine has the most harmful effects are the cardiovascular and nervous system. The adverse effects of homocysteine are achieved by the action of several different mechanisms, such as overactivation of N-methyl-d-aspartate receptors, activation of Toll-like receptor 4, disturbance in Ca2+ handling, increased activity of nicotinamide adenine dinucleotide phosphate-oxidase and subsequent increase of production of reactive oxygen species, increased activity of nitric oxide synthase and nitric oxide synthase uncoupling and consequent impairment in nitric oxide and reactive oxygen species synthesis. Increased production of reactive species during hyperhomocysteinemia is related with increased expression of several proinflammatory cytokines, including IL-1β, IL-6, TNF-α, MCP-1, and intracellular adhesion molecule-1. All these mechanisms contribute to the emergence of diseases like atherosclerosis and related complications such as myocardial infarction, stroke, aortic aneurysm, as well as Alzheimer disease and epilepsy. This review provides evidence that supports the causal role for hyperhomocysteinemia in the development of cardiovascular disease and nervous system disorders.
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Affiliation(s)
- Dragan Djuric
- a Institute of Medical Physiology "Richard Burian" Faculty of Medicine, University of Belgrade, Visegradska 26, Belgrade 11000, Serbia
| | - Vladimir Jakovljevic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia.,c Department of Human Pathology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Trubetskaya st. 8, Moscow 119991, Russia
| | - Vladimir Zivkovic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia
| | - Ivan Srejovic
- b Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, Kragujevac 34000, Serbia
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16
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Bar A, Olkowicz M, Tyrankiewicz U, Kus E, Jasinski K, Smolenski RT, Skorka T, Chlopicki S. Functional and Biochemical Endothelial Profiling In Vivo in a Murine Model of Endothelial Dysfunction; Comparison of Effects of 1-Methylnicotinamide and Angiotensin-converting Enzyme Inhibitor. Front Pharmacol 2017; 8:183. [PMID: 28443021 PMCID: PMC5385379 DOI: 10.3389/fphar.2017.00183] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Accepted: 03/21/2017] [Indexed: 12/20/2022] Open
Abstract
Although it is known that 1-methylnicotinamide (MNA) displays vasoprotective activity in mice, as yet the effect of MNA on endothelial function has not been demonstrated in vivo. Here, using magnetic resonance imaging (MRI) we profile the effects of MNA on endothelial phenotype in mice with atherosclerosis (ApoE/LDLR-/-) in vivo, in comparison to angiotensin (Ang) -converting enzyme (ACE) inhibitor (perindopril), with known vasoprotective activity. On a biochemical level, we analyzed whether MNA- or perindopril-induced improvement in endothelial function results in changes in ACE/Ang II-ACE2/Ang-(1–7) balance, and L-arginine/asymmetric dimethylarginine (ADMA) ratio. Endothelial function and permeability were evaluated in the brachiocephalic artery (BCA) in 4-month-old ApoE/LDLR-/- mice that were non-treated or treated for 1 month or 2 months with either MNA (100 mg/kg/day) or perindopril (10 mg/kg/day). The 3D IntraGate®FLASH sequence was used for evaluation of BCA volume changes following acetylcholine (Ach) administration, and for relaxation time (T1) mapping around BCA to assess endothelial permeability using an intravascular contrast agent. Activity of ACE/Ang II and ACE2/Ang-(1–7) pathways as well as metabolites of L-arginine/ADMA pathway were measured using liquid chromatography/mass spectrometry-based methods. In non-treated 6-month-old ApoE/LDLR-/- mice, Ach induced a vasoconstriction in BCA that amounted to –7.2%. 2-month treatment with either MNA or perindopril resulted in the reversal of impaired Ach-induced response to vasodilatation (4.5 and 5.5%, respectively) and a decrease in endothelial permeability (by about 60% for MNA-, as well as perindopril-treated mice). Improvement of endothelial function by MNA and perindopril was in both cases associated with the activation of ACE2/Ang-(1–7) and the inhibition of ACE/Ang II axes as evidenced by an approximately twofold increase in Ang-(1–9) and Ang-(1–7) and a proportional decrease in Ang II and its active metabolites. Finally, MNA and perindopril treatment resulted in an increase in L-arginine/ADMA ratio by 107% (MNA) and 140% (perindopril), as compared to non-treated mice. Functional and biochemical endothelial profiling in ApoE/LDLR-/- mice in vivo revealed that 2-month treatment with MNA (100 mg/kg/day) displayed a similar profile of vasoprotective effect as 2-month treatment with perindopril (10 mg/kg/day): i.e., the improvement in endothelial function that was associated with the beneficial changes in ACE/Ang II-ACE2/Ang (1–7) balance and in L-arginine/ADMA ratio in plasma.
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Affiliation(s)
- Anna Bar
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian UniversityKrakow, Poland.,Chair of Pharmacology, Jagiellonian University Medical CollegeKrakow, Poland
| | - Mariola Olkowicz
- Department of Biochemistry, Medical University of GdanskGdansk, Poland.,Department of Biotechnology and Food Microbiology, Poznan University of Life SciencesPoznan, Poland
| | - Urszula Tyrankiewicz
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian UniversityKrakow, Poland
| | - Edyta Kus
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian UniversityKrakow, Poland
| | - Krzysztof Jasinski
- Department of Magnetic Resonance Imaging, Institute of Nuclear Physics Polish Academy of SciencesKrakow, Poland
| | | | - Tomasz Skorka
- Department of Magnetic Resonance Imaging, Institute of Nuclear Physics Polish Academy of SciencesKrakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian UniversityKrakow, Poland.,Chair of Pharmacology, Jagiellonian University Medical CollegeKrakow, Poland
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17
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Qin X, Li Y, Sun N, Wang H, Zhang Y, Wang J, Li J, Xu X, Liang M, Nie J, Wang B, Cheng X, Li N, Sun Y, Zhao L, Wang X, Hou FF, Huo Y. Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients. Arterioscler Thromb Vasc Biol 2017; 37:166-172. [PMID: 27834686 DOI: 10.1161/atvbaha.116.308515] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/25/2016] [Indexed: 11/16/2022]
Abstract
Objective—
We aimed to examine whether baseline homocysteine (Hcy) concentrations affect antihypertensive responses to enalapril treatment among previously untreated hypertensive patients (n=10 783) in the CSPPT (China Stroke Primary Prevention Trial).
Approach and Results—
After a 3-week run-in treatment with a daily dose of 10 mg enalapril, eligible hypertensive patients were randomly assigned to a double-blind daily treatment of a tablet of either enalapril (10 mg) and folic acid (0.8 mg) or enalapril (10 mg) alone for a median of 4.5 years. After the 3-week treatment period with enalapril alone, the systolic blood pressure–lowering effect was significantly reduced by 1.39 (95% confidence interval 0.40–2.37) and 3.25 (95% confidence interval 1.98–4.52) mm Hg, respectively, in those with baseline Hcy concentrations of 10 to 15 and ≥15 μmol/L (
P
for trend <0.001) as compared with those with Hcy concentration of <10 μmol/L. Similar results were observed after a 15-week treatment period with enalapril alone. After a median 4.5-year enalapril-based antihypertensive treatment period, compared with those with Hcy concentration of <10 μmol/L, the systolic blood pressure–lowering effect was still significantly reduced by 0.77 (95% confidence interval 0.01–1.53) and 1.70 (95% confidence interval 0.72–2.68) mm Hg, respectively, in those with Hcy concentrations of 10 to 15 and ≥15 μmol/L (
P
for trend <0.001). In addition, participants with higher baseline Hcy concentrations had persistently higher systolic blood pressure levels across the entire study treatment period. Similarly, baseline Hcy concentrations were inversely associated with diastolic blood pressure reduction during the short-term enalapril alone treatment. However, the inverse association between baseline Hcy and diastolic blood pressure reduction was attenuated and became insignificant after the long-term enalapril-based treatment period.
Conclusions—
Elevated Hcy concentrations significantly decreased the antihypertensive effect of the short-term and long-term enalapril-based antihypertensive treatment in previously untreated hypertensive patients.
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Affiliation(s)
- Xianhui Qin
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Youbao Li
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Ningling Sun
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Hong Wang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Yan Zhang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Jiguang Wang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Jianping Li
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Xin Xu
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Min Liang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Jing Nie
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Binyan Wang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Xiaoshu Cheng
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Nanfang Li
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Yingxian Sun
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Lianyou Zhao
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Xiaobin Wang
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Fan Fan Hou
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
| | - Yong Huo
- From the Renal Division, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China (X.Q., Y.L., X.X., M.L., J.N., B.W., F.F.H.); Department of Cardiology, Peking University People’s Hospital, Beijing, China (N.S.); Centers for Metabolic Disease Research, Temple University School of Medicine, PA (H.W.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.Z., J.L., Y.H
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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