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Feng X, Taiwakuli M, Du J, Zhu W, Xu S. Clinical and imaging risk factors for early neurological deterioration and long-term neurological disability in patients with single subcortical small infarction. BMC Neurol 2025; 25:66. [PMID: 39955506 PMCID: PMC11829468 DOI: 10.1186/s12883-025-04067-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/03/2025] [Indexed: 02/17/2025] Open
Abstract
INTRODUCTION This study aims to evaluate the clinical and imaging risk factors for early neurological deterioration (END) and long-term neurological disability in patients with Single subcortical small infarction (SSSI). METHODS We retrospectively included SSSI patients hospitalized. Outcomes were defined as modified Rankin Scale (mRS) score > 2 at follow-up and the occurrence of END during hospitalization. Multivariate logistic regression identified independent predictors of END and long-term outcomes. Stepwise regression analysis was used to develop a predictive model for poor outcomes. The predictive performance of risk factors and the model was assessed using receiver operating characteristic (ROC) curves. RESULTS A total of 289 SSSI patients were included. During hospitalization, 18 patients (6.2%) experienced END, and 29 patients (10%) had neurological disability at a median follow-up of 21.4 (16.7-25.2) months. Multivariate analysis showed the National Institutes of Health Stroke Scale (NIHSS) score(OR 1.43, 95% CI 1.19-1.73, P < 0.001), and neutrophil to high-density lipoprotein cholesterol ratio (NHR) (OR 1.28, 95% CI 1.02-1.60, P = 0.034) were independently associated with END. Age (OR 1.08, 95% CI 1.01-1.15, P = 0.028), NIHSS (OR 1.60, 95% CI 1.29-1.98, P < 0.001), symptomatic intracranial artery stenosis (OR 5.26, 95% CI 1.56-17.71, P = 0.007), lacune number (OR 1.51, 95% CI 1.13-2.04, P = 0.006), the degree of brain atrophy (OR 2.03, 95% CI 1.19-3.46, P = 0.01), and mean hemoglobin concentration (MCHC) (OR 0.96, 95% CI 0.92-0.99, P = 0.04) were independently associated with neurological disability. The predictive model for END (included NIHSS score and NHR level) and long-term neurological disability (included age, NIHSS score, symptomatic intracranial artery stenosis, number of lacunes, and brain atrophy) showed areas under the ROC curve of 0.836 and 0.926, respectively. CONCLUSION High NIHSS and NHR are independent risk factors for END. Age, NIHSS, symptomatic intracranial artery stenosis, the number of lacunes, and brain atrophy are predictors of neurological disability in SSSI patients.
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Affiliation(s)
- Xiao Feng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1095 Jiefang Avenue, Wuhan, 430000, Hubei, P.R. China
| | - Meiherinisa Taiwakuli
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1095 Jiefang Avenue, Wuhan, 430000, Hubei, P.R. China
| | - Junyong Du
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1095 Jiefang Avenue, Wuhan, 430000, Hubei, P.R. China
| | - Wenhao Zhu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1095 Jiefang Avenue, Wuhan, 430000, Hubei, P.R. China
| | - Shabei Xu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, NO.1095 Jiefang Avenue, Wuhan, 430000, Hubei, P.R. China.
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Lee G, Yang J, Kim S, Tran T, Lee SY, Park KH, Kwon S, Chung K, Koh J, Huh YH, Seon J, Kim HA, Chun J, Ryu J. Enhancement of Intracellular Cholesterol Efflux in Chondrocytes Leading to Alleviation of Osteoarthritis Progression. Arthritis Rheumatol 2025; 77:151-162. [PMID: 39262222 PMCID: PMC11782112 DOI: 10.1002/art.42984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 08/26/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
OBJECTIVE Osteoarthritis (OA) is the most common degenerative disease worldwide, with no practical means of prevention and limited treatment options. Recently, our group unveiled a novel mechanism contributing to OA pathogenesis in association with abnormal cholesterol metabolism in chondrocytes. In this study, we aimed to establish a clinical link between lipid profiles and OA in humans, assess the effectiveness of cholesterol-lowering drugs in suppressing OA development in mice, and uncover the cholesterol-lowering mechanisms that effectively impede OA progression. METHODS Five clinically approved cholesterol-lowering drugs (fenofibrate, atorvastatin, ezetimibe, niacin, and lomitapide) were injected into the knee joints or administered with diet to mice with OA who underwent destabilization of the medial meniscus induction and were fed a 2% high-cholesterol diet. Gene expression linked to cholesterol metabolism was determined using microarray analysis. Furthermore, the in vivo functions of these genes were explored through intra-articular injection of either its inhibitor or adenovirus. RESULTS Logistic regression analysis confirmed a close relationship between the diagnostic criteria of hyperlipidemia based on serum lipid levels and OA incidence. Among the cholesterol-lowering drugs examined, fenofibrate exerted the most significant protective effect against cartilage destruction, which was attributed to elevated levels of high-density lipoprotein cholesterol that are crucial for cholesterol efflux. Notably, cholesterol efflux was suppressed during OA progression via down-regulation of apolipoprotein A1-binding protein (AIBP) expression. Overexpression of AIBP effectively inhibits OA progression. CONCLUSION Our results suggest that restoration of cholesterol homeostasis to a normal state through administration of fenofibrate or AIBP overexpression, both of which induce cholesterol efflux, offers an effective therapeutic option for patients with OA.
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Affiliation(s)
- Gyuseok Lee
- Chonnam National UniversityGwangjuRepublic of Korea
| | - Jiye Yang
- Gwangju Institute of Science and TechnologyGwangjuRepublic of Korea
| | - Su‐Jin Kim
- Chonnam National UniversityGwangjuRepublic of Korea
| | | | | | - Ka Hyon Park
- Chonnam National UniversityGwangjuRepublic of Korea
| | | | - Ki‐Ho Chung
- Chonnam National UniversityGwangjuRepublic of Korea
| | | | - Yun Hyun Huh
- Gwangju Institute of Science and TechnologyGwangjuRepublic of Korea
| | - Jong‐Keun Seon
- Chonnam National University Hwasun Hospital and Medical SchoolHwasunRepublic of Korea
| | - Hyun Ah Kim
- Hallym University, Sacred Heart HospitalAnyangRepublic of Korea
| | - Jang‐Soo Chun
- Gwangju Institute of Science and TechnologyGwangjuRepublic of Korea
| | - Je‐Hwang Ryu
- Chonnam National UniversityGwangjuRepublic of Korea
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Montazeri Namin S, Moradi A, Tavolinejad H, Vasheghani-Farahani A, Jalali A, Pashang M, Sadeghian S, Bagheri J, Mansourian S, Mehrani M, Hosseini K, Rashedi S, Tajdini M. Sex-based association between high-density lipoprotein cholesterol and adverse outcomes after coronary artery bypass grafting. BMC Cardiovasc Disord 2024; 24:194. [PMID: 38580951 PMCID: PMC10996185 DOI: 10.1186/s12872-024-03806-1] [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: 08/18/2023] [Accepted: 02/20/2024] [Indexed: 04/07/2024] Open
Abstract
BACKGROUND High-density lipoprotein cholesterol (HDL-C) is shown to be an independent protective factor against coronary artery diseases (CAD). Yet there are limited studies focusing on the association between HDL-C and coronary artery bypass graft (CABG) surgery outcomes. HYPOTHESIS Low levels of HDL-C are associated with higher incidence of adverse outcomes in patients undergoing CABG. METHODS This registry-based study included 17,772 patients who underwent elective isolated CABG between 2007 and 2017. Patients were classified into low and desirable HDL-C groups based on their serum HDL-C levels at admission and were followed for one-year post-surgery. The study population included 13,321 patients with low HDL-C and 4,451 with desirable HDL-C. proportional hazard Cox models were performed to evaluate the association between HDL-C levels and incidence of mortality as well as major adverse cardiovascular and cerebrovascular events (MACCE), while adjusting for potential confounders. Moreover, participants were stratified based on sex and the association was also investigated in each subgroup separately. RESULTS No significant difference was found between the groups regarding incidence of both mortality and MACCE, after adjusting with Inverse Probability Weighting (IPW) [HR (95%CI): 0.84 (0.46-1.53), p-value:0.575 and HR (95% CI): 0.91 (0.56-1.50), p-value:0.733, respectively]. According to the sex-based subgroup analysis, no significant association was observed after adjustment with IPW analysis. However, as we examined the association between the interaction of HDL-C levels, sex and cardiovascular outcomes, we found a significant association (HR;1.19 (95%CI: 1.04-1.45); p = 0.030). CONCLUSION HDL-C level was not associated with either mortality or MACCE during one year after CABG procedure. Sex-based analysis showed that in males, HDL-C is significantly more protective against these outcomes, compared to females. Further studies are necessary to elucidate the exact mechanisms mediating such association.
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Affiliation(s)
- Sara Montazeri Namin
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Moradi
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Tavolinejad
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ali Vasheghani-Farahani
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Arash Jalali
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Pashang
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Sadeghian
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Jamshid Bagheri
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheil Mansourian
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehrani
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kaveh Hosseini
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Rashedi
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Masih Tajdini
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Ou W, Jiang T, Zhang N, Lu K, Weng Y, Zhou X, Wang D, Dong Q, Tang X. Role of HDL cholesterol in anthracycline-induced subclinical cardiotoxicity: a prospective observational study in patients with diffuse large B-cell lymphoma treated with R-CHOP. BMJ Open 2024; 14:e074541. [PMID: 38341200 PMCID: PMC10862278 DOI: 10.1136/bmjopen-2023-074541] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
OBJECTIVES Anthracycline-induced cardiotoxicity is a debilitating cardiac dysfunction for which there are no effective treatments, making early prevention of anthracycline-induced subclinical cardiotoxicity (AISC) crucial. High-density lipoprotein cholesterol (HDL-C) plays a role in cardioprotection, but its impact on AISC remains unclear. Our study aims to elucidate the protective capacity of HDL-C in AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (cyclophosphamide, vincristine, doxorubicin, prednisone and rituximab). DESIGN Prospective observational study. SETTING Conducted in China from September 2020 to September 2022. PARTICIPANTS 70 chemotherapy-naïve patients newly diagnosed with DLBCL who were scheduled to receive the standard dose of R-CHOP; 60 participants included in a case-control study (DOI: 10.1186/s12885-022-10085-6). PRIMARY OUTCOME MEASURES Serum biomarkers, 2D speckle tracking echocardiography and conventional echocardiography were measured at baseline, at the end of the third and sixth cycles of R-CHOP and 6 and 12 months after chemotherapy. RESULTS 24 patients experienced AISC, while 10 did not. 36 patients were lost to follow-up and death. Cox regression analysis showed that higher levels of HDL-C were associated with a significantly lower risk of AISC (unadjusted HR=0.24, 95% CI 0.09 to 0.67, p=0.006; adjusted HR=0.27, 95% CI 0.09 to 0.79, p=0.017). Patients without AISC had a more stable and higher HDL-C level during the follow-up period. HDL-C levels significantly decreased from the end of the third cycle of chemotherapy to the end of the sixth cycle of chemotherapy in all patients (p=0.034), and particularly in the AISC group (p=0.003). The highest level of HDL-C was significantly higher in patients without AISC than in those with AISC (1.52±0.49 vs 1.22±0.29, p=0.034). CONCLUSIONS Our study suggests that higher HDL-C levels may associate with lower AISC risk in patients with DLBCL treated with R-CHOP. HDL-C could be a cardioprotective target, but further research is needed to confirm its benefits and limitations. STUDY REGISTRATION NUMBER Study registration number: ChiCTR2100054721.
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Affiliation(s)
- Wenxin Ou
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tiantian Jiang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Nan Zhang
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Lu
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yue Weng
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Zhou
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong Wang
- Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Dong
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqiong Tang
- Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Chen T, Wu S, Feng L, Long S, Liu Y, Lu W, Chen W, Hong G, Zhou L, Wang F, Luo Y, Zou H. The Association of HDL2b with Metabolic Syndrome Among Normal HDL-C Populations in Southern China. Diabetes Metab Syndr Obes 2024; 17:363-377. [PMID: 38288339 PMCID: PMC10822767 DOI: 10.2147/dmso.s446859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 01/16/2024] [Indexed: 01/31/2024] Open
Abstract
Background The annual prevalence of metabolic syndrome (MetS) is increasing. Therefore, early screening and recognition of MetS are critical. This study aimed to evaluate the association between high-density lipoprotein (HDL) subclasses and MetS and to examine whether they could serve as early indicators in a Chinese community-based population with normal high-density lipoprotein cholesterol (HDL-C) levels. Methods We used microfluidic chip technology to measure HDL subclasses in 463 people with normal HDL levels in 2018. We assessed how HDL subclasses correlated with and predicted insulin resistance (IR) and metabolic syndrome (MetS), evaluated by homeostatic model insulin resistance index (HOMA-IR) and the 2009 International Diabetes Federation (IDF), the American Heart Association (AHA), and the National Heart, Lung, and Blood Institute (NHLBI) criteria, respectively. We used correlation tests and ROC curves for the analysis. Results The results indicate that there was a negative association between HDL2b% and the risk of IR and MetS in both sexes. Subjects in the highest quartile of HDL2b% had a significantly lower prevalence of IR and MetS than those in the lowest quartile (P<0.01). Correlation analysis between HDL2b% and metabolic risk factors showed that HDL2b% had a stronger association with these factors than HDL-C did in both sexes. ROC curve analysis also showed that HDL2b% had significant diagnostic value for IR and MetS compared to other lipid indicators. Conclusion This study showed that MetS alters the distribution of HDL subclasses even when HDL-C levels are within the normal range. HDL-2b% has better diagnostic value for IR and MetS than HDL-C alone and may be a useful marker for early screening.
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Affiliation(s)
- Tong Chen
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National Regional Key Technology Engineering Laboratory for Medical Ultrasound School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, People’s Republic of China
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China
| | - Shiquan Wu
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Ling Feng
- Department of Nephrology, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China
| | - SiYu Long
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Yu Liu
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National Regional Key Technology Engineering Laboratory for Medical Ultrasound School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, People’s Republic of China
| | - WenQian Lu
- Department of Medicine, The Chinese University of Hong Kong, Shenzhen, People’s Republic of China
| | - Wenya Chen
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Guoai Hong
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Li Zhou
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Fang Wang
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Yuechan Luo
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
| | - Hequn Zou
- Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China
- Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Medicine, The Chinese University of Hong Kong, Shenzhen, People’s Republic of China
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Carmo HRP, Bonilha I, Barreto J, Tognolini M, Zanotti I, Sposito AC. High-Density Lipoproteins at the Interface between the NLRP3 Inflammasome and Myocardial Infarction. Int J Mol Sci 2024; 25:1290. [PMID: 38279290 PMCID: PMC10816227 DOI: 10.3390/ijms25021290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024] Open
Abstract
Despite significant therapeutic advancements, morbidity and mortality following myocardial infarction (MI) remain unacceptably high. This clinical challenge is primarily attributed to two significant factors: delayed reperfusion and the myocardial injury resulting from coronary reperfusion. Following reperfusion, there is a rapid intracellular pH shift, disruption of ionic balance, heightened oxidative stress, increased activity of proteolytic enzymes, initiation of inflammatory responses, and activation of several cell death pathways, encompassing apoptosis, necroptosis, and pyroptosis. The inflammatory cell death or pyroptosis encompasses the activation of the intracellular multiprotein complex known as the NLRP3 inflammasome. High-density lipoproteins (HDL) are endogenous particles whose components can either promote or mitigate the activation of the NLRP3 inflammasome. In this comprehensive review, we explore the role of inflammasome activation in the context of MI and provide a detailed analysis of how HDL can modulate this process.
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Affiliation(s)
- Helison R. P. Carmo
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), Division of Cardiology, State University of Campinas (UNICAMP), Campinas 13084-971, SP, Brazil; (H.R.P.C.); (I.B.); (J.B.); (A.C.S.)
| | - Isabella Bonilha
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), Division of Cardiology, State University of Campinas (UNICAMP), Campinas 13084-971, SP, Brazil; (H.R.P.C.); (I.B.); (J.B.); (A.C.S.)
| | - Joaquim Barreto
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), Division of Cardiology, State University of Campinas (UNICAMP), Campinas 13084-971, SP, Brazil; (H.R.P.C.); (I.B.); (J.B.); (A.C.S.)
| | | | - Ilaria Zanotti
- Department of Food and Drug, University of Parma, 43124 Parma, Italy;
| | - Andrei C. Sposito
- Atherosclerosis and Vascular Biology Laboratory (Aterolab), Division of Cardiology, State University of Campinas (UNICAMP), Campinas 13084-971, SP, Brazil; (H.R.P.C.); (I.B.); (J.B.); (A.C.S.)
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Chen C, Chang CC, Lee IT, Huang CY, Lin FY, Lin SJ, Chen JW, Chang TT. High-density lipoprotein protects vascular endothelial cells from indoxyl sulfate insults through its antioxidant ability. Cell Cycle 2023; 22:2409-2423. [PMID: 38129288 PMCID: PMC10802207 DOI: 10.1080/15384101.2023.2296184] [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: 05/17/2023] [Revised: 11/24/2023] [Accepted: 12/10/2023] [Indexed: 12/23/2023] Open
Abstract
Chronic kidney disease (CKD) patients have a high risk of cardiovascular disease. Indoxyl sulfate (IS) is a uremic toxin that has been shown to inhibit nitric oxide production and cause cell senescence by inducing oxidative stress. High-density lipoprotein (HDL) has a protective effect on the cardiovascular system; however, its impacts on IS-damaged endothelial cells are still unknown. This study aimed to explore the effects of exogenous supplement of HDL on vascular endothelial cells in a uremia-mimic environment. Tube formation, migration, adhesion, and senescence assays were used to evaluate the cell function of human aortic endothelial cells (HAECs). Reactive oxygen species generation was measured by using Amplex red assay. L-NAME and MCI186 were used as a nitric oxide synthase inhibitor and a free radical scavenger, respectively. HDL exerted anti-inflammatory and antioxidant effects via HIF-1α/HO-1 activation and IL-1β/TNF-α/IL-6 inhibition in IS-stimulated HAECs. HDL improved angiogenesis ability through upregulating Akt/eNOS/VEGF/SDF-1 in IS-stimulated HAECs. HDL decreased endothelial adhesiveness via downregulating VCAM-1 and ICAM-1 in IS-stimulated HAECs. Furthermore, HDL reduced cellular senescence via upregulating SIRT1 and downregulating p53 in IS-stimulated HAECs. Importantly, the above beneficial effects of HDL were mainly due to its antioxidant ability. In conclusion, HDL exerted a comprehensive protective effect on vascular endothelial cells against damage from IS through its antioxidant ability. The results of this study might provide a theoretical basis for potential HDL supplementation in CKD patients with endothelial damage.
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Affiliation(s)
- Ching Chen
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chi Chang
- Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
| | - I-Ta Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Yao Huang
- Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Feng-Yen Lin
- Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Shing-Jong Lin
- Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Jaw-Wen Chen
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Research, Taipei Medical University Hospital, Taipei, Taiwan
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-Ting Chang
- Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan
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Yan J, Yang S, Han L, Ba X, Shen P, Lin W, Li T, Zhang R, Huang Y, Huang Y, Qin K, Wang Y, Tu S, Chen Z. Dyslipidemia in rheumatoid arthritis: the possible mechanisms. Front Immunol 2023; 14:1254753. [PMID: 37954591 PMCID: PMC10634280 DOI: 10.3389/fimmu.2023.1254753] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/09/2023] [Indexed: 11/14/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called "lipid paradox". The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.
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Affiliation(s)
- Jiahui Yan
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Sisi Yang
- Department of Geriatrics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Liang Han
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Xin Ba
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Pan Shen
- Department of Rheumatology and Immunology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Weiji Lin
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Li
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ruiyuan Zhang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Ying Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yao Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Kai Qin
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Yu Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Shenghao Tu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
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Florida EM, Li H, Rodante J, Teague HL, Playford MP. Myeloperoxidase and its negative relationship with cholesterol efflux capacity in patients with psoriasis: results from an observational cohort study. J Transl Med 2023; 21:743. [PMID: 37864160 PMCID: PMC10589920 DOI: 10.1186/s12967-023-04506-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 10/22/2023] Open
Affiliation(s)
- Elizabeth M Florida
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Haiou Li
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - J Rodante
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - H L Teague
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Martin P Playford
- Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
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Mousa H, Thanassoulas A, Zughaier SM. ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein. Biochem Biophys Rep 2023; 34:101445. [PMID: 36915826 PMCID: PMC10006442 DOI: 10.1016/j.bbrep.2023.101445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/02/2023] Open
Abstract
Background HDL possesses anti-inflammatory properties, however, the exact mechanism is not fully understood. Endotoxin is a potent inducers of TLR4 signaling, leading to inflammatory mediators' release. It has been estimated that TLR4 recognizes about 5% of circulating lipopolysaccharide whereas 95% is cleared by plasma lipoproteins, mainly HDL. ApoM is required for HDL biogenesis and 95% of plasma ApoM is found associated with HDL, both are significantly reduced during sepsis. Aim The aim of this study is to investigate whether ApoM binds endotoxin and contributes to anti-inflammatory activity of HDL. Methods Isothermal Titration Calorimetry (ITC) was used to determine the binding of ultrapure E. coli LPS to the recombinant ApoM protein. Purified human HDL and recombinant ApoM was used to investigate LPS neutralization using human and murine macrophages and computational simulation was performed. Result ApoM shows high affinity for E. coli LPS, forming 1:1 complexes with Kd values below 1 μΜ, as revealed by ITC. The binding process is strongly exothermic and enthalpy-driven (ΔrH = -36.5 kJ/mol), implying the formation of an extensive network of interactions between ApoM and LPS in the bound state. Computational simulation also predicted high-affinity binding between ApoM and E. coli LPS and the best scoring models showed E. coli LPS docking near the calyx of ApoM without blocking the pocket. The biological significance of this interaction was further demonstrated in macrophages where purified HDL neutralized an E. coli LPS effect and significantly reduced TNFα release from human THP-1 cells. Conclusion ApoM binds LPS to facilitate endotoxin neutralization and clearance by HDL.
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Affiliation(s)
- Hanaa Mousa
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, P.O. Box 2713, Qatar
| | - Angelos Thanassoulas
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, P.O. Box 2713, Qatar
| | - Susu M Zughaier
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, P.O. Box 2713, Qatar
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11
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Xia W, Yu H, Wang G. Coronary Artery Disease with Elevated Levels of HDL Cholesterol Is Associated with Distinct Lipid Signatures. Metabolites 2023; 13:695. [PMID: 37367853 DOI: 10.3390/metabo13060695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/28/2023] Open
Abstract
Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography-tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.
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Affiliation(s)
- Wanying Xia
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, No. 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Haiyi Yu
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, No. 49 North Garden Road, Haidian District, Beijing 100191, China
| | - Guisong Wang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, No. 49 North Garden Road, Haidian District, Beijing 100191, China
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12
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Sim RZH, Tham YC, Betzler BK, Zhou L, Wang X, Sabanayagam C, Cheung GCM, Wong TY, Cheng CY, Nusinovici S. Relationships between Lipid-Related Metabolites and Age-Related Macular Degeneration Vary with Complement Genotype. OPHTHALMOLOGY SCIENCE 2022; 2:100211. [PMID: 36531576 PMCID: PMC9755028 DOI: 10.1016/j.xops.2022.100211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 06/17/2023]
Abstract
OBJECTIVE Lipid dysregulation and complement system (CS) activation are 2 important pathophysiology pathways for age-related macular degeneration (AMD). We hypothesized that the relationship between lipids and AMD may also differ according to CS genotype profile. Thus, the objective was to investigate the relationships between lipid-related metabolites and AMD according to CS genotypes. DESIGN Population-based cross-sectional study. PARTICIPANTS A total of 6947 participants from Singapore Epidemiology of Eye Diseases study with complete relevant data were included. METHODS We investigated a total of 32 blood lipid-related metabolites from nuclear magnetic resonance metabolomics data including lipoproteins and their subclasses, cholesterols, glycerides, and phospholipids, as well as 4 CS single nucleotide polymorphisms (SNPs): rs10922109 (complement factor H), rs10033900 (complement factor I), rs116503776 (C2-CFB-SKIV2L), and rs2230199 (C3). We first investigated the associations between AMD and the 32 lipid-related metabolites using multivariable logistic regression models. Then, to investigate whether the effect of lipid-related metabolites on AMD differ according to the CS SNPs, we tested the possible interactions between the CS SNPs and the lipid-related metabolites. MAIN OUTCOME MEASURES Age-related macular degeneration was defined using the Wisconsin grading system. RESULTS Among the 6947 participants, the prevalence of AMD was 6.1%, and the mean age was 58.3 years. First, higher levels of cholesterol in high-density lipoprotein (HDL) and medium and large HDL particles were associated with an increased risk of AMD, and higher levels of serum total triglycerides (TG) and several very-low-density lipoprotein subclass particles were associated with a decreased risk of AMD. Second, these lipids had significant interaction effects on AMD with 2 CS SNPs: rs2230199 and rs116503776 (after correction for multiple testing). For rs2230199, in individuals without risk allele, higher total cholesterol in HDL2 was associated with an increased AMD risk (odds ratio [OR] per standard deviation increase, 1.20; 95% confidence interval (CI), 1.06-1.37; P = 0.005), whereas, in individuals with at least 1 risk allele, higher levels of these particles were associated with a decreased AMD risk (OR, 0.69; 95% CI, 0.45-1.05; P = 0.079). Conversely, for rs116503776, in individuals without risk allele, higher serum total TG were associated with a decreased AMD risk (OR, 0.84; 95% CI, 0.74-0.95; P = 0.005), whereas, in individuals with 2 risk alleles, higher levels of these particles were associated with an increased risk of AMD (OR, 2.3, 95% CI, 0.99-5.39, P = 0.054). CONCLUSIONS Lipid-related metabolites exhibit opposite directions of effects on AMD according to CS genotypes. This indicates that lipid metabolism and CS may have synergistic interplay in the AMD pathogenesis.
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Key Words
- AMD, age-related macular degeneration
- Age-related macular degeneration
- CFH, complement factor H
- CS, complement system
- Complement system
- HDL, high-density lipoprotein
- Lipids
- Metabolites
- NMR, nuclear magnetic resonance
- OR, odds ratio
- RPE, retinal pigment epithelium
- SNP, single nucleotide polymorphism
- TG, triglycerides
- VLDL, very-low–density lipoprotein
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Affiliation(s)
- Ralene Zi Hui Sim
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
| | - Yih-Chung Tham
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
| | | | - Lei Zhou
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
| | - Xiaomeng Wang
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore
| | - Charumathi Sabanayagam
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
| | - Gemmy Chiu Ming Cheung
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
| | - Tien Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Simon Nusinovici
- Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
- Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore
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Dong Q, Ou W, Wang M, Jiang T, Weng Y, Zhou X, Tang X. Study on influencing factors of anthracycline-induced subclinical cardiotoxicity in DLBCL patients administered (R)-CHOP. BMC Cancer 2022; 22:988. [PMID: 36115970 PMCID: PMC9482309 DOI: 10.1186/s12885-022-10085-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 09/12/2022] [Indexed: 07/10/2024] Open
Abstract
Background Anthracycline-induced cardiotoxicity is an irreversible cardiac cell injury. Therefore, it’s very important to identify influencing factors of anthracycline-induced subclinical cardiotoxicity (AISC). This study was designed to analyze the influencing factors of AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with the (R)-CHOP chemotherapy regimen. Methods This is an ongoing observational prospective clinical trial. All patients underwent conventional echocardiography and speckle tracking echocardiography at the time of enrollment and during treatment. Changes of global longitudinal peak systolic strain were assessed after 3 cycles of (R)-CHOP chemotherapy, and patients were divided into the AISC and No-AISC groups. Demographic data, clinical variables, and biochemical variables were measured. Regression models, receiver operating characteristic curve analysis, and difference values were used to explore the relationships between variables and AISC. Results Among 70 patients who completed 3 cycles of (R)-CHOP chemotherapy, 26 developed AISC. In multiple logistic regression, HDL-C (P = 0.047), ApoA1 (P = 0.022), TG (P = 0.029) and e’ (P = 0.008) were associated with AISC. The combination of HDL-C and NT-proBNP had the highest area under curves (AUC) for the diagnosis of AISC than HDL-C and NT-proBNP alone (AUC = 0.752, 95%CI: 0.63–0.87, P = 0.001). Between the No-AISC and AISC groups, there was no significant difference in HDL-C, ApoA1, and e’ at baseline and after 3 cycles of chemotherapy, respectively. The dynamic changes of HDL-C, ApoA1, and e’ from baseline to the end of the 3rd cycle of chemotherapy showed statistically significant differences. Conclusions HDL-C, ApoA1, TG, and e’ are independent predictive factors in DLBCL cases treated with the (R)-CHOP chemotherapy regimen. The combination of HDL-C and NT-proBNP may improve the predictive ability for AISC in patients with DLBCL administered 3 cycles of (R)-CHOP chemotherapy. Dynamic changes of HDL-C, ApoA1, and e’ may be meaningful for predicting AISC. Trial registration Our study was registered in the Chinese Clinical Trial Registry (Approval ID. ChiCTR2100054721 http://www.chictr.org.cn/showproj.aspx?proj=145082).
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14
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Liu SL, Feng BY, Song QR, Zhang YM, Wu SL, Cai J. Neutrophil to high-density lipoprotein cholesterol ratio predicts adverse cardiovascular outcomes in subjects with pre-diabetes: a large cohort study from China. Lipids Health Dis 2022; 21:86. [PMID: 36057713 PMCID: PMC9441053 DOI: 10.1186/s12944-022-01695-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
Background This study aimed to examine whether the neutrophil to high-density lipoprotein cholesterol ratio (NHR) can predict cardiovascular outcomes in normoglycemic individuals with elevated fasting glucose levels. Methods A total of 130,801 participants with normal blood glucose levels were enrolled in the Kailuan study. Participants were categorized according to NHR quartiles and further divided into normal glucose regulation (NGR) and pre-diabetes (pre-DM) subgroups. The follow-up endpoint was major adverse cardiovascular events (CVE), including stroke and myocardial infarction. Results Over a median of 12.53 (8.95–13.08) years of follow-up, subjects with NHR levels in the highest quartile experienced more CVE than those with NHR levels in the lowest quartile. Multivariate Cox analyses showed that continuous changes in NHR (hazard ratio, 1.21; 95% confidence interval [CI], 1.15–1.28) and the highest quartile of NHR (hazard ratio, 1.30; 95% CI, 1.21–1.39) were independent predictors of CVE (all P < 0.001). Furthermore, when participants were categorized by both NHR quartile and glucose metabolism status, the NHR level in the highest quartile plus pre-DM group was associated with a 1.60-fold (95% CI, 1.38–1.86; P < 0.001] higher risk of CVE than that in the lowest quartile plus normoglycemic group. Significantly, the addition of NHR only, presence of pre-DM only, or combination of NHR and pre-DM to the prediction algorithm, including traditional risk factors, improved the C-statistic by 0.19, 0.05, and 0.23 (all P < 0.001). Conclusions Elevated NHR or fasting blood glucose level were independently associated with a higher risk of CVE among normoglycemic individuals. Moreover, pre-DM participants with high NHR levels tended to have worse prognosis, suggesting that NHR could provide greater risk stratification value than traditional risk factors for subjects with pre-DM. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-022-01695-x.
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Affiliation(s)
- Shuo-Lin Liu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine. Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
| | - Bao-Yu Feng
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100730, China
| | - Qi-Rui Song
- Hypertension Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China
| | - Ying-Mei Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine. Key Laboratory of Viral Heart Diseases, National Health Commission. Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China
| | - Shuo-Ling Wu
- Department of Cardiology, Kailuan General Hospital, Tangshan, China.
| | - Jun Cai
- Hypertension Center, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease of China, National Center for Cardiovascular Diseases of China, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
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15
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Zhang Q, Jiang Z, Xu Y. HDL and Oxidation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1377:63-77. [PMID: 35575921 DOI: 10.1007/978-981-19-1592-5_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In this chapter, we will focus on HDLs' activity of inhibiting LDL oxidation and neutralizing some other oxidants. ApoA-I was known as the main antioxidant component in HDLs. The regulation of antioxidant capacity of HDL is mainly exhibited in regulation of apoA-I and alterations at the level of the HDL lipidome and the modifications of the proteome, especially MPO and PON1. HDL oxidation will influence the processes of inflammation and cholesterol transport, which are important processes in atherosclerosis, metabolic diseases, and many other diseases. In a word, HDL oxidation might be an effective antioxidant target in treatment of many diseases.
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Affiliation(s)
- Qi Zhang
- The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing, China
| | - Zongzhe Jiang
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yong Xu
- Department of Endocrinology and Metabolism, Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Nephropathy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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16
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Deng S, Liu J, Niu C. HDL and Cholesterol Ester Transfer Protein (CETP). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1377:13-26. [PMID: 35575918 DOI: 10.1007/978-981-19-1592-5_2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Cholesterol ester transfer protein (CETP) is important clinically and is one of the major targets in cardiovascular disease studies. With high conformational flexibility, its tunnel structure allows unforced movement of high-density lipoproteins (HDLs), VLDLs, and LDLs. Research in reverse cholesterol transports (RCT) reveals that the regulation of CETP activity can change the concentration of cholesteryl esters (CE) in HDLs, VLDLs, and LDLs. These molecular insights demonstrate the mechanisms of CETP activities and manifest the correlation between CETP and HDL. However, animal and cell experiments focused on CETP give controversial results. Inhibiting CETP is found to be beneficial to anti-atherosclerosis in terms of increasing plasma HDL-C, while it is also claimed that CETP weakens atherosclerosis formation by promoting RCT. Currently, the CETP-related drugs are still immature. Research on CETP inhibitors is targeted at improving efficacy and minimizing adverse reactions. As for CETP agonists, research has proved that they also can be used to resist atherosclerosis.
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Affiliation(s)
- Siying Deng
- Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, China
| | | | - Chenguang Niu
- Key Laboratory of Clinical Resources Translation, First Affiliated Hospital, Henan University, Kaifeng, Henan, China.
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17
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Frangie C, Daher J. Role of myeloperoxidase in inflammation and atherosclerosis (Review). Biomed Rep 2022; 16:53. [PMID: 35620311 PMCID: PMC9112398 DOI: 10.3892/br.2022.1536] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 04/12/2022] [Indexed: 11/29/2022] Open
Abstract
Myeloperoxidase (MPO) belongs to the heme peroxidase family, which includes a set of enzymes with potent oxidoreductase activity. MPO is considered an important part of the innate immune system's microbicidal arm and is secreted by neutrophils and macrophages. Interestingly, this enzyme has been implicated in the pathogenesis of several diseases including atherosclerosis. MPO is ubiquitous in atherosclerotic lesions and contributes to the initiation and progression of the disease primarily by oxidizing low-density lipoprotein (LDL) particles. MPO is the only human enzyme with the ability to produce hypochlorous acid (HOCl) at physiological chloride concentrations and HOCl-LDL epitopes were shown to be present inside atheromatous lesions making it a physiologically relevant model for the oxidation of LDL. It has been shown that MPO modified LDL is not able to bind to the native LDL receptor and is recognized instead by scavenger receptors on both endothelial cells and macrophages, which can lead to endothelial dysfunction and foam cell formation, respectively; both of which are instrumental in the progression of the disease. Meanwhile, several studies have proposed MPO as a biomarker for cardiovascular diseases where high levels of this enzyme were linked to an increased risk of developing coronary artery disease. Overall, there is sufficient evidence supporting the value of MPO as a crucial player in health and disease. Thus, future research should be directed towards investigating the still unknown processes associated with this enzyme. This may assist in better understanding the pathophysiological role of MPO, as well in the development of therapeutic strategies for protecting against the deleterious effects of MPO in numerous pathologies such as atherosclerosis.
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Affiliation(s)
- Christian Frangie
- Department of Biology, Faculty of Arts and Sciences, University of Balamand, El‑Koura 100, Lebanon
| | - Jalil Daher
- Department of Biology, Faculty of Arts and Sciences, University of Balamand, El‑Koura 100, Lebanon
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18
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Opoku E, Berisha S, Brubaker G, Robinet P, Smith JD. Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice. PLoS One 2022; 17:e0259751. [PMID: 35120132 PMCID: PMC8815868 DOI: 10.1371/journal.pone.0259751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/25/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Transgenic overexpression of apolipoprotein A-I (apoA1) has been shown to delay atherosclerosis lesion progression and promote lesion regression in mouse models; however, apoA1 is subject to oxidation by myeloperoxidase (MPO) and loss of function. The activity of oxidant resistant human apoA1 was compared to unmodified human apoA1 in mouse models of atherosclerosis progression and regression. METHODS AND RESULTS Human apoA1 and the MPO oxidant resistant 4WF isoform transgenic mice were bred to LDL receptor deficient (LDLr KO) mice and fed a western-type diet. High level expression of these human apoA1 isoforms did not lead to increased HDL-cholesterol levels on the LDLr KO background. In males and females, lesion progression was studied over time, and both apoA1 and 4WF transgenic mice vs. LDLr KO mice had significant and similar delayed lesion progression and reduced non-HDL cholesterol. Using time points with equivalent lesion areas, lesion regression was initiated by feeding the mice a low-fat control diet containing a microsomal triglyceride transfer protein inhibitor for 7 weeks. Lesions regressed more in the male apoA1 and 4WF transgenics vs. the LDLr KO, but the 4WF isoform was not superior to the unmodified isoform in promoting lesion regression. CONCLUSIONS Both human apoA1 and the 4WF MPO oxidant resistant apoA1 isoform delayed lesion progression and promoted lesion regression in LDLr KO mice, with more pronounced effects in males than females; moreover, the 4WF isoform functioned similarly to the unmodified human apoA1 isoform.
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Affiliation(s)
- Emmanuel Opoku
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Stela Berisha
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Gregory Brubaker
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Peggy Robinet
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Jonathan D. Smith
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
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Doğan K, Şeneş M, Karaca A, Kayalp D, Kan S, Gülçelik NE, Aral Y, Yücel D. HDL subgroups and their paraoxonase-1 activity in the obese, overweight and normal weight subjects. Int J Clin Pract 2021; 75:e14969. [PMID: 34626508 DOI: 10.1111/ijcp.14969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/10/2021] [Accepted: 10/07/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Obesity and overweight are significant public health problems because of higher risk for coronary artery disease (CAD). It is very important to determine new predictive markers to identify the CAD risk in obese and overweight. To aim this, we analysed HDL-C subgroups (HDL2-C and HDL3-C) and their paraoxonase-1 (PON-1) activity in obese, overweight and normal weight subjects. METHOD 71 obese, 40 overweight and 30 healthy subjects as a control group were enrolled the study. Serum lipids levels were determined with enzymatic colorimetric method. Further, PON-1 activities and HDL-C levels were determined by spectrophotometric methods. Non-HDL3-C concentrations were calculated with the subtraction of HDL3-C from total HDL-C. RESULTS The mean serum levels of total HDL-C, HDL3-C, Non-HDL3-C and ApoA1 were higher in control group than obese and overweight groups. There were a statistically significant difference between obese and control group in terms of Lp(a), hsCRP and HOMA index. Higher total PON-1, non-HDL3 PON-1 and HDL3 PON-1 activities were found in the control group compared with obese and overweight groups. Total HDL was weakly negative correlated with the HOMA index, BMI and waist circumference. There was a weak negative correlation between non-HDL3-C and waist circumference. CONCLUSION Altered HDL-subgroups pattern and decreased PON-1 activities may cause increased risk for CVD in obese and overweight individuals. Therefore determination of HDL subgroups and their PON-1 activity may improve risk prediction compared with measuring total HDL-C levels and its PON-1 activity alone. Body weight and insulin resistance appear to have a role in the decreased HDL-C levels and PON-1activity in obese. Further studies should be conducted to shed more light on impacts of these markers in CVD.
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Affiliation(s)
- Kübra Doğan
- Department of Clinical Biochemistry, Sivas Numune State Hospital, Ministry of Health, Sivas, Turkey
| | - Mehmet Şeneş
- Department of Clinical Biochemistry, Ankara Training and Research Hospital, Ministry of Health Ankara, Turkey
| | - Anara Karaca
- Department of Endocrinology and Metabolism, Ankara Training and Research Hospital, Ministry of Health Ankara, Turkey
| | - Damla Kayalp
- Department of Clinical Biochemistry, Yozgat City Hospital, Ministry of Health, Yozgat, Turkey
| | - Seyfullah Kan
- Department of Endocrinology and Metabolism, Faculty of Medicine, Süleyman Demirel University, Isparta, Turkey
| | - Neşe Ersöz Gülçelik
- Department of Endocrinology and Metabolism, Gülhane Training and Research Hospital, Ministry of Health Ankara, Turkey
| | - Yalçın Aral
- Department of Endocrinology and Metabolism, Faculty of Medicine, Yozgat Bozok University, Yozgat, Turkey
| | - Doğan Yücel
- Department of Clinical Biochemistry, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey
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20
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Shao S, Zhou K, Liu X, Liu L, Wu M, Deng Y, Duan H, Li Y, Hua Y, Wang C. Predictive Value of Serum Lipid for Intravenous Immunoglobulin Resistance and Coronary Artery Lesion in Kawasaki Disease. J Clin Endocrinol Metab 2021; 106:e4210-e4220. [PMID: 33837779 DOI: 10.1210/clinem/dgab230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Indexed: 11/19/2022]
Abstract
CONTEXT Intravenous immunoglobulin (IVIG) resistance and coronary artery lesions (CALs) prediction are pivotal topic of interests in Kawasaki disease (KD). However, data on the predictive value of lipid profile for both IVIG resistance and CALs are limited. PURPOSE To investigate the predictive validity of lipid profile for IVIG resistance and CALs in KD. DESIGN Prospective cohort study. SETTING West China Second University Hospital. PATIENTS 363 KD patients were divided into the initial IVIG-resistant group and initial IVIG-responsive group; repeated IVIG-resistant group and repeated IVIG-responsive group; CAL+ group and CAL- group. MAIN OUTCOME MEASURES Validity of lipid profile in predicting IVIG resistance and CALs. RESULTS Triglycerides were significantly higher whereas total cholesterol (TC), high-densisty lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein A (Apo A) were significantly lower in initial IVIG-resistant subjects, with cut-off values of 1.625 mmol/L, 3.255 mmol/L, 0.475 mmol/L, 1.965 mmol/L, and 0.665 g/L, yielding sensitivities of 52%, 70%, 52%, 61%, and 50% and specificities of 68%, 53%, 78%, 71%, and 81%, respectively. TC, LDL-C, and Apo A levels were significantly lower in repeated IVIG-resistant subjects, with cut-off values of 3.20 mmol/L, 1.78 mmol/L, and 0.605 g/L, producing sensitivities of 91%, 70%, and 57% and specificities of 55%, 67%, and 70%, respectively. Apo A level was significantly lower in the CAL+ group, with cut-off value of 0.805 g/L, yielding sensitivity of 66% and specificity of 54%. CONCLUSIONS Lipid profiles were significantly dysregulated in KD patients suffering IVIG resistance and CALs. Some of them, such as LDL-C and Apo A, could serve as complementary laboratory markers for predicting both IVIG resistance and CALs.
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Affiliation(s)
- Shuran Shao
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- West China Medical School of Sichuan University, Chengdu, Sichuan, China
| | - Kaiyu Zhou
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education Chengdu, Sichuan, China
- Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoliang Liu
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lei Liu
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- West China Medical School of Sichuan University, Chengdu, Sichuan, China
| | - Mei Wu
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuxin Deng
- Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hongyu Duan
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education Chengdu, Sichuan, China
- Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yifei Li
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education Chengdu, Sichuan, China
- Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yimin Hua
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education Chengdu, Sichuan, China
- Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chuan Wang
- Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- The Cardiac development and early intervention unit, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education Chengdu, Sichuan, China
- Key Laboratory of Development and Diseases of Women and Children of Sichuan Province, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
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21
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Garcia C, Blesso CN. Antioxidant properties of anthocyanins and their mechanism of action in atherosclerosis. Free Radic Biol Med 2021; 172:152-166. [PMID: 34087429 DOI: 10.1016/j.freeradbiomed.2021.05.040] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/14/2021] [Accepted: 05/29/2021] [Indexed: 12/20/2022]
Abstract
Atherosclerosis develops due to lipid accumulation in the arterial wall and sclerosis as result of increased hyperlipidemia, oxidative stress, lipid oxidation, and protein oxidation. However, improving antioxidant status through diet may prevent the progression of atherosclerotic cardiovascular disease. It is believed that polyphenol-rich plants contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are flavonoid polyphenols with antioxidant properties that have been associated with reduced risk of cardiovascular disease. The consumption of anthocyanins increases total antioxidant capacity, antioxidant defense enzymes, and HDL antioxidant properties by several measures in preclinical and clinical populations. Anthocyanins appear to impart antioxidant actions via direct antioxidant properties, as well as indirectly via inducing intracellular Nrf2 activation and antioxidant gene expression. These actions counter oxidative stress and inflammatory signaling in cells present in atherosclerotic plaques, including macrophages and endothelial cells. Overall, anthocyanins may protect against atherosclerosis and cardiovascular disease through their effects on cellular antioxidant status, oxidative stress, and inflammation; however, their underlying mechanisms of action appear to be complex and require further elucidation.
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Affiliation(s)
- Chelsea Garcia
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, 06269, United States
| | - Christopher N Blesso
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT, 06269, United States.
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22
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Jin Z, Zhou L, Tian R, Lu N. Myeloperoxidase Targets Apolipoprotein A-I for Site-Specific Tyrosine Chlorination in Atherosclerotic Lesions and Generates Dysfunctional High-Density Lipoprotein. Chem Res Toxicol 2021; 34:1672-1680. [PMID: 33861588 DOI: 10.1021/acs.chemrestox.1c00086] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We previously demonstrated that apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), is an important target for myeloperoxidase (MPO)-catalyzed tyrosine chlorination in the circulation of subjects with cardiovascular diseases. Oxidation of apoA-I by MPO has been reported to deprive HDL of its protective properties. However, the potential effects of MPO-mediated site-specific tyrosine chlorination of apoA-I on dysfunctional HDL formation and atherosclerosis was unclear. Herein, Tyr192 in apoA-I was found to be the major chlorination site in both lesion and plasma HDL from humans with atherosclerosis, while MPO binding to apoA-I was demonstrated by immunoprecipitation studies in vivo. In vitro, MPO-mediated damage of lipid-free apoA-I impaired its ability to promote cellular cholesterol efflux by the ABCA1 pathway, whereas oxidation to lipid-associated apoA-I inhibited lecithin:cholesterol acyltransferase activation, two key steps in reverse cholesterol transport. Compared with native apoA-I, apoA-I containing a Tyr192 → Phe mutation was moderately resistant to oxidative inactivation by MPO. In high-fat-diet-fed apolipoprotein E-deficient mice, compared with native apoA-I, subcutaneous injection with oxidized apoA-I (MPO treated) failed to mediate the lipid content in aortic plaques while mutant apoA-I (Tyr192 → Phe) showed a slightly stronger ability to reduce the lipid content in vivo. Our observations suggest that oxidative damage of apoA-I and HDL involves MPO-dependent site-specific tyrosine chlorination, raising the feasibility of producing MPO-resistant forms of apoA-I that have stronger antiatherosclerotic activity in vivo.
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Affiliation(s)
- Zelong Jin
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Jiangxi Key Laboratory of Green Chemistry, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
| | - Lan Zhou
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Jiangxi Key Laboratory of Green Chemistry, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
| | - Rong Tian
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Jiangxi Key Laboratory of Green Chemistry, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
| | - Naihao Lu
- Key Laboratory of Functional Small Organic Molecule, Ministry of Education; Jiangxi Key Laboratory of Green Chemistry, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China
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23
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Negi P, Heikkilä T, Tallgren T, Malmi P, Lund J, Sinisalo J, Metso J, Jauhiainen M, Pettersson K, Lamminmäki U, Lövgren J. Three two-site apoA-I immunoassays using phage expressed detector antibodies - Preliminary clinical evaluation with cardiac patients. J Pharm Biomed Anal 2020; 194:113772. [PMID: 33309125 DOI: 10.1016/j.jpba.2020.113772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 11/25/2022]
Abstract
High density lipoproteins (HDL) are a heterogenous group of subpopulations differing in protein/lipid composition and in their anti-atherogenic function. There is a lack of specific and robust assays which can target the functionality of HDL with respect to atherosclerosis. With recently generated CAD HDL targeted, single chain recombinant antibodies (scFvs) we set out to design and optimize apo A-I tests to compare it with conventional HDL-C and apo A-I analyses for diagnosis and risk assessment of coronary artery disease (CAD) and its outcome. Three highly sensitive two-site apo A-I assays: 022-454, 109-121 and 110-525 were optimized. A preliminary clinical evaluation of these assays, after proper sample dilution procedure, was performed using samples derived from 195 chest pain patients (myocardial infarction (MI), n = 86 and non-MI, n = 109), collected at the time of admission and at discharge from hospital (hospital stay ≤ 24 h). The clinical performance of the assays was compared with apo A-I measured with polyclonal anti-apo A-I antibody using conventional ELISA. Apo A-I data was in addition compared with HDL-C concentration of the samples. The concentration of apo A-I was significantly lower in MI patients than in non-MI individuals with assay 022-454 (admission and discharge samples, P < 0.0001 and = 0.004); assay 109-121 (admission and discharge samples, P = 0.04 and 0.0009), and, ELISA based apo A-I test (admission and discharge samples, P = 0.008 and < 0.0001). HDL-C (admission and discharge samples, P = 0.002 and P = 0.01) was also significantly lower in MI patients. In Kaplan- Meier analysis, two-site assay 109-121 assay predicted mortality from admission samples at 1.5 yrs (whole cohort, P = 0.01 and in MI patients, P = 0.05) and at 6 months (whole cohort, P = 0.04). Assay 110-525 predicted mortality at 1.5 yrs from admission samples of non-MI patients (P = 0.01) and at 6 months from whole discharge sample cohort (P = 0.04). Polyclonal anti-apo A-I based conventional assay predicted mortality at 1.5 yrs from admission samples of whole cohort (P = 0.03). Two-site apo A-I assay 022-454 and HDL-C provided no capability of predicting mortality in the whole cohort or any sub-group. In conclusion, two of the tested recombinant apo A-I antibody combinations (sc 109-121 and sc 110-525) display promising outcome to improve diagnosis and prediction of future cardiac events in cardiac patients over polyclonal apo A-I ELISA and HDL-C assays. The noted differences, while interesting, are preliminary and need however to be verified in extensive cohorts of pathological cardiac conditions and healthy controls.
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Affiliation(s)
- Priyanka Negi
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland.
| | - Taina Heikkilä
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
| | - Terhi Tallgren
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
| | - Päivi Malmi
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
| | - Juha Lund
- Heart Center, Turku University Hospital, Finland
| | - Juha Sinisalo
- Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland
| | - Jari Metso
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland; National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research, Biomedicum, Helsinki, Finland; National Institute for Health and Welfare, Genomics and Biomarkers Unit, Biomedicum, Helsinki, Finland
| | - Kim Pettersson
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
| | - Urpo Lamminmäki
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
| | - Janita Lövgren
- Department of Biochemistry, Division of Biotechnology, University of Turku, Turku, Finland
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24
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Arnhold J. The Dual Role of Myeloperoxidase in Immune Response. Int J Mol Sci 2020; 21:E8057. [PMID: 33137905 PMCID: PMC7663354 DOI: 10.3390/ijms21218057] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/25/2020] [Accepted: 10/28/2020] [Indexed: 12/14/2022] Open
Abstract
The heme protein myeloperoxidase (MPO) is a major constituent of neutrophils. As a key mediator of the innate immune system, neutrophils are rapidly recruited to inflammatory sites, where they recognize, phagocytose, and inactivate foreign microorganisms. In the newly formed phagosomes, MPO is involved in the creation and maintenance of an alkaline milieu, which is optimal in combatting microbes. Myeloperoxidase is also a key component in neutrophil extracellular traps. These helpful properties are contrasted by the release of MPO and other neutrophil constituents from necrotic cells or as a result of frustrated phagocytosis. Although MPO is inactivated by the plasma protein ceruloplasmin, it can interact with negatively charged components of serum and the extracellular matrix. In cardiovascular diseases and many other disease scenarios, active MPO and MPO-modified targets are present in atherosclerotic lesions and other disease-specific locations. This implies an involvement of neutrophils, MPO, and other neutrophil products in pathogenesis mechanisms. This review critically reflects on the beneficial and harmful functions of MPO against the background of immune response.
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Affiliation(s)
- Jürgen Arnhold
- Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, 04 107 Leipzig, Germany
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25
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Sun X, Chen R, Yan G, Chen Z, Yuan H, Huang W, Lu Y. Gender-specific associations between apolipoprotein A1 and arterial stiffness in patients with nonalcoholic fatty liver disease. PeerJ 2020; 8:e9757. [PMID: 32874784 PMCID: PMC7441919 DOI: 10.7717/peerj.9757] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
Background Lipid metabolism factors may play an important role in the progression of nonalcoholic fatty liver disease (NAFLD) and its related cardiovascular dysfunctions. The study aims to assess whether Apolipoprotein A-1 (ApoA1) was associated with vascular stiffness in NAFLD patients. Methods From 2012 to 2013, we included 2,295 non-alcohol users with fatty liver disease (1,306 male patients) and completely excluded subjects who drank any alcohol ever to eliminate the effect of alcohol intake. The serum ApoA1 levels and the brachial-ankle pulse wave velocity (baPWV) were measured. Results The baPWV in men was much higher than in female patients (1,412.79 cm/s vs. 1,358.69 cm/s, P < 0.001). ApoA1 level was positively associated with baPWV odd ratio (OR), 4.18; 95% confidence interval (CI) [1.16-15.1], P < 0.05) in patients with AST/ALT < 1 and (OR, 4.70; 95% CI [1.36-16.23], P < 0.05) in patients with AST/ALT ≥ 1 respectively. Only arterial stiffness in men was associated with ApoA1 (OR, 3.96; 95% CI [1.29-12.30], P < 0.05) in logistics regression models adjusted for age, gender, body mass index, education attainment, physical activity, smoking, history of hypertension and high-density lipoprotein. The relationship between ApoA1 and baPWV in male NAFLD patients remained significant (confidence, 156.42; 95% CI [49.34-263.50], P < 0.05) in the fully adjusted linear regression model. Conclusion The serum ApoA1 was associated with arterial stiffness in male NAFLD patients. Increased ApoA1 level should be considered as an independent risk factor for arterial stiffness in male NAFLD patients, suggesting that NAFLD may alter arterial stiffness by "ApoA1-related" mechanism in men.
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Affiliation(s)
- Xulong Sun
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China.,Department of General Surgery, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Ruifang Chen
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Guangyu Yan
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Zhiheng Chen
- Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Hong Yuan
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Wei Huang
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China
| | - Yao Lu
- Clinical Research Center, The Third Xiangya Hospital of Central South University, Changsha, China.,Department of Life Science and Medicine, King's College London, London, UK
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26
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Dewhurst-Trigg R, Wadley AJ, Woods RM, Sherar LB, Bishop NC, Hulston CJ, Markey O. Short-term High-fat Overfeeding Does Not Induce NF-κB Inflammatory Signaling in Subcutaneous White Adipose Tissue. J Clin Endocrinol Metab 2020; 105:5813979. [PMID: 32232380 DOI: 10.1210/clinem/dgaa158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 03/27/2020] [Indexed: 12/22/2022]
Abstract
CONTEXT It is unclear how white adipose tissue (WAT) inflammatory signaling proteins respond during the early stages of overnutrition. OBJECTIVE To investigate the effect of short-term, high-fat overfeeding on fasting abdominal subcutaneous WAT total content and phosphorylation of proteins involved in nuclear factor-κB (NF-κB) inflammatory signaling, systemic metabolic and inflammatory biomarkers. DESIGN Individuals consumed a high-fat (65% total energy from total fat), high-energy (50% above estimated energy requirements) diet for 7 days. RESULTS Fifteen participants (aged 27 ± 1 years; body mass index 24.4 ± 0.6 kg/m2) completed the study. Body mass increased following high-fat overfeeding (+1.2 ± 0.2 kg; P < 0.0001). However, total content and phosphorylation of proteins involved in NF-κB inflammatory signaling were unchanged following the intervention. Fasting serum glucose (+0.2 ± 0.0 mmol/L), total cholesterol (+0.4 ± 0.1 mmol/L), low-density lipoprotein cholesterol (+0.3 ± 0.1 mmol/L), high-density lipoprotein cholesterol (+0.2 ± 0.0 mmol/L), and lipopolysaccharide-binding protein (LBP; +4.7 ± 2.1 µg/mL) increased, whereas triacylglycerol concentrations (-0.2 ± 0.1 mmol/L) decreased following overfeeding (all P < 0.05). Systemic biomarkers (insulin, soluble cluster of differentiation 14 [CD14], C-reactive protein, interleukin-6, tumor necrosis factor-α and monocyte chemoattractant protein-1) and the proportion and concentration of circulating CD14+ monocytes were unaffected by overfeeding. CONCLUSION Acute lipid oversupply did not impact on total content or phosphorylation of proteins involved in WAT NF-κB inflammatory signaling, despite modest weight gain and metabolic alterations. Systemic LBP, which is implicated in the progression of low-grade inflammation during the development of obesity, increased in response to a 7-day high-fat overfeeding period.
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Affiliation(s)
- Rebecca Dewhurst-Trigg
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Alex J Wadley
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Rachel M Woods
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Lauren B Sherar
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Nicolette C Bishop
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Carl J Hulston
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
| | - Oonagh Markey
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, Reading, UK
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27
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Altered HDL metabolism in metabolic disorders: insights into the therapeutic potential of HDL. Clin Sci (Lond) 2020; 133:2221-2235. [PMID: 31722013 DOI: 10.1042/cs20190873] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 12/18/2022]
Abstract
Metabolic disorders are associated with an increased risk of cardiovascular disease (CVD), and are commonly characterized by a low plasma level of high-density lipoprotein cholesterol (HDL-C). Although cholesterol lowering medications reduce CVD risk in these patients, they often remain at increased risk of CVD. Therapeutic strategies that raise HDL-C levels and improve HDL function are a potential treatment option for reducing residual CVD risk in these individuals. Over the past decade, understanding of the metabolism and cardioprotective functions of HDLs has improved, with preclinical and clinical studies both indicating that the ability of HDLs to mediate reverse cholesterol transport, inhibit inflammation and reduce oxidation is impaired in metabolic disorders. These cardioprotective effects of HDLs are supported by the outcomes of epidemiological, cell and animal studies, but have not been confirmed in several recent clinical outcome trials of HDL-raising agents. Recent studies suggest that HDL function may be clinically more important than plasma levels of HDL-C. However, at least some of the cardioprotective functions of HDLs are lost in acute coronary syndrome and stable coronary artery disease patients. HDL dysfunction is also associated with metabolic abnormalities. This review is concerned with the impact of metabolic abnormalities, including dyslipidemia, obesity and Type 2 diabetes, on the metabolism and cardioprotective functions of HDLs.
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28
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Kluck GEG, Durham KK, Yoo JA, Trigatti BL. High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity. Front Cardiovasc Med 2020; 7:65. [PMID: 32411725 PMCID: PMC7198830 DOI: 10.3389/fcvm.2020.00065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 04/06/2020] [Indexed: 01/01/2023] Open
Abstract
Cardiovascular disease and cancer are the leading causes of death in developed societies. Despite their effectiveness, many cancer therapies exhibit deleterious cardiovascular side effects such as cardiotoxicity and heart failure. The cardiotoxic effects of anthracyclines such as doxorubicin are the most well-characterized of cardiotoxic anti-cancer therapies. While other anti-neoplastic drugs also induce cardiotoxicity, often leading to heart failure, they are beyond the scope of this review. This review first summarizes the mechanisms of doxorubicin-induced cardiotoxicity. It then reviews emerging preclinical evidence that high density lipoprotein and its precursor protein apolipoprotein A1, which are known for their protective effects against ischemic cardiovascular disease, may also protect against doxorubicin-induced cardiotoxicity both directly and indirectly, when used therapeutically.
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Affiliation(s)
- George E. G. Kluck
- Department of Biochemistry and Biomedical Sciences, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Kristina K. Durham
- Faculty of Health Sciences, Institute of Applied Health Sciences, School of Rehabilitation Sciences, McMaster University, Hamilton, ON, Canada
| | - Jeong-Ah Yoo
- Department of Biochemistry and Biomedical Sciences, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
| | - Bernardo L. Trigatti
- Department of Biochemistry and Biomedical Sciences, Thrombosis and Atherosclerosis Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada
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The association of plasma lipids with white blood cell counts: Results from the Multi-Ethnic Study of Atherosclerosis. J Clin Lipidol 2019; 13:812-820. [DOI: 10.1016/j.jacl.2019.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/02/2019] [Accepted: 07/07/2019] [Indexed: 02/06/2023]
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Abstract
Type 1 diabetes mellitus (T1DM) is associated with premature cardiovascular disease (CVD), but the underlying mechanisms remain poorly understood. The American Diabetes Association and the European Association for the Study of Diabetes recently updated their position statement on the management of type 2 diabetes mellitus (T2DM) to include additional focus on cardiovascular risk; improved management of risk factors in T1DM is also needed. There are important differences in the pathophysiology of CVD in T1DM and T2DM. Hyperglycaemia appears to have a more profound effect on cardiovascular risk in T1DM than T2DM, and other risk factors appear to cause a synergistic rather than additive effect, so achievement of treatment targets for all recognized risk factors is crucial to reducing cardiovascular risk. Here we discuss the evidence for addressing established cardiovascular risk factors, candidate biomarkers and surrogate measurements, and possible interventions.
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Affiliation(s)
- Jonathan Schofield
- Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WU, UK.
| | - Jan Ho
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WU, UK
- Cardiovascular Trials Unit, University Department of Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK
| | - Handrean Soran
- Cardiovascular Research Group, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9WU, UK
- Cardiovascular Trials Unit, University Department of Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK
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31
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Poteryaeva ON, Usynin IF. [Antidiabetic role of high density lipoproteins]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2019; 64:463-471. [PMID: 30632974 DOI: 10.18097/pbmc20186406463] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Disturbance in lipid metabolism can be both a cause and a consequence of the development of diabetes mellitus (DM). One of the most informative indicator of lipid metabolism is the ratio of atherogenic and antiatherogenic fractions of lipoproteins and their protein components. The review summarizes literature data and own results indicating the important role of high-density lipoprotein (HDL) and their main protein component, apolipoprotein A-I (apoA-I), in the pathogenesis of type 2 DM. On the one hand, HDL are involved in the regulation of insulin secretion by b-cells and insulin-independent absorption of glucose. On the other hand, insulin resistance and hyperglycemia lead to a decrease in HDL levels and cause modification of their protein component. In addition, HDL, possessing anti-inflammatory and mitogenic properties, provide anti-diabetic protection through systemic mechanisms. Thus, maintaining a high concentration of HDL and apoA-I in blood plasma and preventing their modification are important issues in the context of prevention and treatment of diabetes.
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Affiliation(s)
- O N Poteryaeva
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
| | - I F Usynin
- Institute of Biochemistry, Federal Research Center of Fundamental and Translation Medicine, Novosibirsk, Russia
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32
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Mogarekar MR, Dhabe MG, Palmate MM. PON1 arylesterase activity, HDL functionality and their correlation in malnourished children. J Pediatr Endocrinol Metab 2019; 32:321-326. [PMID: 30875327 DOI: 10.1515/jpem-2018-0327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 01/29/2019] [Indexed: 11/15/2022]
Abstract
Background The study was done to assess high-density lipoprotein (HDL) functionality and to correlate this with paraoxonase 1 (PON1) activity in malnourished children. It aimed to find the effect of malnutrition on changes in PON1 activity, HDL functionality, lipid profile and lipid hydroperoxide formation. Methods This case control study included 30 malnourished children (up to age 5 years) and 30 healthy controls in the paediatric inpatient department of SRTR Government Medical College Ambajogai, India. Clinically diagnosed cases depending on anthropometric indices were selected. Serum PON1 activity by using phenyl acetate as a substrate, HDL functionality by haemin by its protection on H2O2 and haemin induced LDL oxidation, lipid profile by routine enzymatic methods and lipid hydroperoxide using the FOX2 assay were measured. Results Malnourished children had significantly decreased PON1 activity (106.6 ± 12.74** vs. 132.23 ± 28.49 IU/L), HDL functionality (116.55 ± 8** vs. 132.29 ± 10.9%), total cholesterol (TC) (102.5 ± 16** vs. 116.4 ± 12.65 mg/dL), HDL-cholesterol (C) (33.41 ± 9.74** vs. 40.55 ± 5.85 mg/dL) and reduced total protein level (5.56 ± 0.91* vs. 6.06 ± 1.055) higher triglycerides (TG) (146.76 ± 34.97* vs. 125.96 ± 17.21 mg/dL) level and total hydroperoxide (TPX) levels (5.568 ± 1.70** vs. 3.22 ± 1.52 μM/L). *p < 0.05 **p < 0.001. PON1 activity (r2 = 0.576) and TC (r2 = 0.567) shows significant positive correlation with HDL functionality. PON1 activity, HDL-C, HDL functionality and TPX shows independent contribution towards malnutrition in children in multivariate and univariate logistic regression. TC lost its significance in multivariate regression. Conclusions Malnutrition leads to decrease in HDL functionality and increase in hydroperoxide levels with a decrease in PON1 activity.
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Stefanović A, Zeljković A, Vekić J, Spasojević-Kalimanovska V, Jelić-Ivanović Z, Spasić S. Dyslipidemia in type 2 diabetes mellitus. ARHIV ZA FARMACIJU 2019. [DOI: 10.5937/arhfarm1905338s] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Robertson MD, Pedersen C, Hinton PJ, Mendis ASJR, Cani PD, Griffin BA. Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men. Nutr Metab Cardiovasc Dis 2018; 28:1296-1303. [PMID: 30459055 DOI: 10.1016/j.numecd.2018.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/19/2018] [Accepted: 07/19/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Serum lipids and lipoproteins are established biomarkers of cardiovascular disease risk that could be influenced by impaired gut barrier function via effects on the absorption of dietary and biliary cholesterol. The aim of this study was to examine the potential relationship between gut barrier function (gut permeability) and concentration of serum lipids and lipoproteins, in an ancillary analysis of serum samples taken from a previous study. METHODS AND RESULTS Serum lipids, lipoproteins and functional gut permeability, as assessed by the percentage of the urinary recovery of 51Cr-labelled EDTA absorbed within 24 h, were measured in a group of 30 healthy men. Serum lipopolysaccharide, high sensitivity C-reactive protein and interleukin-6 were also measured as markers of low-grade inflammation. The group expressed a 5-fold variation in total gut permeability (1.11-5.03%). Gut permeability was unrelated to the concentration of both serum total and low density lipoprotein (LDL)-cholesterol, but was positively associated with serum high density lipoprotein (HDL)-cholesterol (r = 0.434, P = 0.015). Serum HDL-cholesterol was also positively associated with serum endotoxaemia (r = 0.415, P = 0.023). CONCLUSION The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein.
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Affiliation(s)
- M D Robertson
- Nutritional Sciences, University of Surrey, Guildford, UK.
| | - C Pedersen
- Nutritional Sciences, University of Surrey, Guildford, UK
| | - P J Hinton
- Medical Physics, Royal Surrey County Hospital, Guildford, UK
| | - A S J R Mendis
- Nutritional Sciences, University of Surrey, Guildford, UK
| | - P D Cani
- WELBIO - Walloon Excellence in Life Sciences and BIOtechnology, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - B A Griffin
- Nutritional Sciences, University of Surrey, Guildford, UK
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35
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Cholesteryl ester transfer protein: An enigmatic pharmacology – Antagonists and agonists. Atherosclerosis 2018; 278:286-298. [DOI: 10.1016/j.atherosclerosis.2018.09.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/04/2018] [Accepted: 09/25/2018] [Indexed: 12/31/2022]
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Millar CL, Duclos Q, Garcia C, Norris GH, Lemos BS, DiMarco DM, Fernandez ML, Blesso CN. Effects of Freeze-Dried Grape Powder on High-Density Lipoprotein Function in Adults with Metabolic Syndrome: A Randomized Controlled Pilot Study. Metab Syndr Relat Disord 2018; 16:464-469. [DOI: 10.1089/met.2018.0052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Affiliation(s)
- Courtney L. Millar
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Quinn Duclos
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Chelsea Garcia
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Gregory H. Norris
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Bruno S. Lemos
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Diana M. DiMarco
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
| | - Maria Luz Fernandez
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut
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Divya G, Jayaprakash NS, Venkataraman K. Development and Characterization of Monoclonal Antibodies Against Nitro- 166Tyrosine of High-Density Lipoprotein: Apolipoprotein A1. Monoclon Antib Immunodiagn Immunother 2018; 37:167-174. [PMID: 30132720 DOI: 10.1089/mab.2018.0018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Apolipoprotein A1 (ApoA1) of the high-density lipoprotein (HDL) plays a cardinal role in alleviating atherosclerosis in various ways. Its role in reverse cholesterol transport is preeminent. However, the ApoA1 undergoes oxidation under chronic inflammatory conditions and these oxidations are mediated by myeloperoxidase. It has been reported that the oxidation of the amino acids such as methionine, tyrosine, and tryptophan residues at specific sites of ApoA1 renders it not only dysfunctional but also proinflammatory and proatherogenic. Thus, assessing the quality of ApoA1 and, in turn, that of HDL in circulating blood can serve as an early diagnostic tool for cardiovascular diseases (CVDs). In this study, we developed monoclonal antibodies (mAbs) specific to modified ApoA1 with its tyrosine residue at the 166th position nitrated to 3-nitrotyrosine. A 20 amino acid peptide around the modification of interest was designed using an antigenicity prediction tool. The peptide was custom synthesized with ovalbumin as conjugate and used as an antigen to immunize BALB/c mice. Hybridomas were obtained by fusion of Sp2/0 mouse myeloma cells with spleen cells from the immunized mouse. A hybridoma clone 2E5B7, thus developed and characterized, was found to secrete mAb of the desired specificity and sensitivity against nitrated 166Tyrosine. The lowest concentration of the antigen that could be detected by the mAb with confidence was 15 ng. The mAb was able to detect nitrated 166Tyrosine peptide ovalbumin conjugate antigen spiked in human plasma with high specificity. The generated mAb could be potentially used in immuno-based diagnostic systems to screen the quality of HDL and in turn assess CVD risks in humans.
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Affiliation(s)
- Guntur Divya
- Advanced Centre for BioSeparation Technology, Vellore Institute of Technology , Vellore, India
| | - N S Jayaprakash
- Advanced Centre for BioSeparation Technology, Vellore Institute of Technology , Vellore, India
| | - Krishnan Venkataraman
- Advanced Centre for BioSeparation Technology, Vellore Institute of Technology , Vellore, India
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Sini S, Deepa D, Harikrishnan S, Jayakumari N. Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease. J Biochem Mol Toxicol 2018; 32:e22192. [PMID: 29992715 DOI: 10.1002/jbt.22192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/22/2018] [Accepted: 06/15/2018] [Indexed: 11/06/2022]
Abstract
High density lipoprotein (HDL)-macrophage interactions have the potential to modulate macrophage function in a beneficial way to prevent the development of lipid-loaded foam cell formation in atherosclerosis. Although HDL is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. Here, we examined the effect of dysfunctional-HDL from patients with coronary artery disease, on macrophage function in comparison to functional-HDL from controls. Exposure of macrophages to dysfunctional-HDL for 24 h resulted significant increase in cellular oxidative stress, cholesterol, and cytotoxicity. It also stimulated mitochondrial membrane depolarization, DNA damage, apoptosis, and cleavage of poly (ADP-ribose) polymerase, which are characteristics of proapoptotic pathways. In contrast, functional-HDL treatment maintained cholesterol homeostasis, essential membrane potential, DNA integrity, and cell survival. These results demonstrate that HDL from coronary artery disease (CAD) patient promotes proatherogenic effects that in turn trigger macrophage apoptosis, an important feature in atherogenesis and thereby providing new insight in our understanding of the atherogenic mechanisms.
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Affiliation(s)
- S Sini
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India
| | - D Deepa
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India
| | - S Harikrishnan
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India
| | - N Jayakumari
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, India
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Boer RE, Giménez-Bastida JA, Boutaud O, Jana S, Schneider C, Sulikowski GA. Total Synthesis and Biological Activity of the Arachidonic Acid Metabolite Hemiketal E 2. Org Lett 2018; 20:4020-4022. [PMID: 29916257 DOI: 10.1021/acs.orglett.8b01578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The total synthesis of hemiketal E2 (HKE2) has been accomplished using a gold(I)-mediated cycloisomerization followed by oxidation of the enol ether product to introduce a unique keto-hemiketal, the core structure of HKE2. Synthetic hemiketal E2 reproduced biosynthetically derived HKE2 in the inhibition of human platelet aggregation.
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Affiliation(s)
- Robert E Boer
- Department of Chemistry , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
| | - Juan Antonio Giménez-Bastida
- Department of Pharmacology , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
| | - Olivier Boutaud
- Department of Pharmacology , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
| | - Somnath Jana
- Department of Chemistry , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
| | - Claus Schneider
- Department of Pharmacology , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
| | - Gary A Sulikowski
- Department of Chemistry , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States.,Department of Pharmacology , Vanderbilt University, Vanderbilt Institute of Chemical Biology Nashville , Tennessee 37232 , United States
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40
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Chen X, Duong MN, Nicholls SJ, Bursill C. Myeloperoxidase modification of high-density lipoprotein suppresses human endothelial cell proliferation and migration via inhibition of ERK1/2 and Akt activation. Atherosclerosis 2018; 273:75-83. [DOI: 10.1016/j.atherosclerosis.2018.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 03/09/2018] [Accepted: 04/06/2018] [Indexed: 10/17/2022]
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Singh K, Rohatgi A. Examining the paradox of high high-density lipoprotein and elevated cardiovascular risk. J Thorac Dis 2018; 10:109-112. [PMID: 29600034 PMCID: PMC5863140 DOI: 10.21037/jtd.2017.12.97] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 12/12/2017] [Indexed: 01/28/2023]
Affiliation(s)
- Kavisha Singh
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Anand Rohatgi
- Division of Cardiology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
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Park KH, Yadav D, Kim SJ, Kim JR, Cho KH. Slim Body Weight Is Highly Associated With Enhanced Lipoprotein Functionality, Higher HDL-C, and Large HDL Particle Size in Young Women. Front Endocrinol (Lausanne) 2018; 9:406. [PMID: 30072955 PMCID: PMC6060307 DOI: 10.3389/fendo.2018.00406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/29/2018] [Indexed: 11/19/2022] Open
Abstract
There has been no information about the correlations between body weight distribution and lipoprotein metabolism in terms of high-density lipoproteins-cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP). In this study, we analyzed the quantity and quality of HDL correlations in young women (21.5 ± 1.2-years-old) with a slim (n = 21, 46.2 ± 3.8 kg) or plump (n = 30, 54.6 ± 4.4 kg) body weight. Body weight was inversely correlated with the percentage of HDL-C in total cholesterol (TC). The plump group showed 40% higher body fat (26 ± 3 %) and 86% more visceral fat mass (VFM, 1.3 ± 0.3 kg) than the slim group, which showed 18 ± 2% body fat and 0.7 ± 0.2 kg of VFM. Additionally, the plump group showed 20% higher TC, 58% higher triglyceride (TG), and 12% lower HDL-C levels in serum. The slim group showed 34% higher apoA-I but 15% lower CETP content in serum compared to the plump group. The slim group showed a 13% increase in particle size and 1.9-fold increase in particle number with enhanced cholesterol efflux activity. Although the plump group was within a normal body mass index (BMI) range, its lipid profile and lipoprotein properties were distinctly different from those of the slim group in terms of CETP mass and activity, HDL functionality, and HDL particle size.
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Affiliation(s)
- Ki-Hoon Park
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, South Korea
- LipoLab, Gyeongsan, South Korea
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, South Korea
- LipoLab, Gyeongsan, South Korea
| | - Suk-Jeong Kim
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, South Korea
- LipoLab, Gyeongsan, South Korea
| | - Jae-Ryong Kim
- Department of Biochemistry and Molecular Biology, Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, South Korea
| | - Kyung-Hyun Cho
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Protein Sensor, Yeungnam University, Gyeongsan, South Korea
- LipoLab, Gyeongsan, South Korea
- *Correspondence: Kyung-Hyun Cho
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Molina-Sánchez P, Jorge I, Martinez-Pinna R, Blanco-Colio LM, Tarin C, Torres-Fonseca MM, Esteban M, Laustsen J, Ramos-Mozo P, Calvo E, Lopez JA, Ceniga MVD, Michel JB, Egido J, Andrés V, Vazquéz J, Meilhac O, Burillo E, Lindholt JS, Martin-Ventura JL. ApoA-I/HDL-C levels are inversely associated with abdominal aortic aneurysm progression. Thromb Haemost 2017; 113:1335-46. [DOI: 10.1160/th14-10-0874] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 01/21/2015] [Indexed: 12/18/2022]
Abstract
SummaryAbdominal aortic aneurysm (AAA) evolution is unpredictable, and there is no therapy except surgery for patients with an aortic size > 5 cm (large AAA). We aimed to identify new potential biomarkers that could facilitate prognosis and treatment of patients with AAA. A differential quantitative proteomic analysis of plasma proteins was performed in AAA patients at different stages of evolution [small AAA (aortic size=3�5cm) vs large AAA] using iTRAQ labelling, highthroughput nano-LC-MS/MS and a novel multi-layered statistical model. Among the proteins identified, ApoA-I was decreased in patients with large AAA compared to those with small AAA. These results were validated by ELISA on plasma samples from small (n=90) and large AAA (n=26) patients (150 ± 3 vs 133 ± 5 mg/dl, respectively, p< 0.001). ApoA-I levels strongly correlated with HDL-Cholesterol (HDL-C) concentration (r=0.9, p< 0.001) and showed a negative correlation with aortic size (r=-0.4, p< 0.01) and thrombus volume (r=-0.3, p< 0.01), which remained significant after adjusting for traditional risk factors. In a prospective study, HDL-C independently predicted aneurysmal growth rate in multiple linear regression analysis (n=122, p=0.008) and was inversely associated with need for surgical repair (Adjusted hazard ratio: 0.18, 95 % confidence interval: 0.04�0.74, p=0.018). In a nation-wide Danish registry, we found lower mean HDL-C concentration in large AAA patients (n=6,560) compared with patients with aorto-iliac occlusive disease (n=23,496) (0.89 ± 2.99 vs 1.59 ± 5.74 mmol/l, p< 0.001). Finally, reduced mean aortic AAA diameter was observed in AngII-infused mice treated with ApoA-I mimetic peptide compared with saline-injected controls. In conclusion, ApoAI/ HDL-C systemic levels are negatively associated with AAA evolution. Therapies targeting HDL functionality could halt AAA formation.
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Williams SA, Murthy AC, DeLisle RK, Hyde C, Malarstig A, Ostroff R, Weiss SJ, Segal MR, Ganz P. Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib. Circulation 2017; 137:999-1010. [PMID: 28974520 PMCID: PMC5839936 DOI: 10.1161/circulationaha.117.028213] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 09/08/2017] [Indexed: 01/10/2023]
Abstract
Supplemental Digital Content is available in the text. Background: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics. Methods: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death. Results: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk. Conclusions: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.
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Affiliation(s)
| | | | | | - Craig Hyde
- University of California, San Francisco. Pfizer Inc., Worldwide Research and Development, Groton, CT (C.H.)
| | - Anders Malarstig
- Pfizer Inc., Worldwide Research and Development, Stockholm, Sweden (A.M.)
| | - Rachel Ostroff
- SomaLogic, Inc., Boulder, CO (S.A.W., R.K.D., R.O., S.J.W.)
| | - Sophie J Weiss
- SomaLogic, Inc., Boulder, CO (S.A.W., R.K.D., R.O., S.J.W.)
| | - Mark R Segal
- Department of Epidemiology and Biostatistics (M.R.S.)
| | - Peter Ganz
- Department of Medicine (A.C.M., P.G.) .,Division of Cardiology, Zuckerberg San Francisco General Hospital, CA (P.G.)
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Chen X, Duong MN, Psaltis PJ, Bursill CA, Nicholls SJ. High-density lipoproteins attenuate high glucose-impaired endothelial cell signaling and functions: potential implications for improved vascular repair in diabetes. Cardiovasc Diabetol 2017; 16:121. [PMID: 28962618 PMCID: PMC5622442 DOI: 10.1186/s12933-017-0605-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Accepted: 09/22/2017] [Indexed: 12/16/2022] Open
Abstract
Background Abnormalities of endothelial cell function are proposed to be a critical factor underlying adverse cardiovascular outcomes in the setting of hyperglycaemia. While high-density lipoproteins (HDL) have been demonstrated to be cardioprotective, the impact on the endothelium in hyperglycaemia has not been fully elucidated. Methods Human umbilical vein endothelial cells (HUVECs) were exposed to high-glucose conditions using dextrose, the main isoform of glucose, and native HDL. HUVEC proliferation and migration were determined. The key signalling pathways that regulate endothelial cell function were also characterized. Results Increasing concentrations of dextrose resulted in significant reductions in HUVEC proliferation, this was attenuated by coincubation with HDL. In support of this, HDL was also found to rescue dextrose impaired expression of PCNA and the activation (phosphorylation) of the key transcription factor for proliferation ERK. Dextrose also dose-dependently inhibited HUVEC migration, which was mitigated by co-incubation with HDL. Consistent with this, HDL prevented dextrose-induced inhibition of p38 phosphorylation, responsible for cell migration. Finally, phosphorylation of the pro-survival transcription factor Akt was dose-dependently inhibited by dextrose, however, this was completely rescued by co-administration with HDL. Conclusion Dextrose-induced hyperglycaemia causes the impairment of endothelial cell proliferation and migration and inhibits the activation of ERK, p38 and Akt pathways. The protective effects of HDL in this milieu highlights the potential for HDL to improve vascular repair in patients with impaired glucose homeostasis.
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Affiliation(s)
- Xing Chen
- Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - My-Ngan Duong
- Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA. .,Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia. .,South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, SA, 5001, Australia.
| | - Peter J Psaltis
- Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Christina A Bursill
- Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
| | - Stephen J Nicholls
- Department of Cell Biology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA.,Heart Health, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia
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Abstract
High-density lipoproteins (HDLs) can inhibit inflammatory cytokine expression on innate immune cells, but sometimes they promote cytokine production as suggested in a recent article in Cell Metabolism by van der Vorst et al. (2017). Kopecky et al. point out that the origin, handling, and storage conditions of HDL preparations dictate their functional properties and can specifically affect immune cells to evoke a pro-inflammatory response.
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Affiliation(s)
- Chantal Kopecky
- Faculty of Medicine, School of Medical Sciences, University of New South Wales, Sydney NSW 2031, Australia
| | - Georg Michlits
- Department of Internal Medicine III, Division of Nephrology & Dialysis, Medical University of Vienna, 1090 Vienna, Austria
| | - Marcus D Säemann
- 6(th) Medical Department for Nephrology and Dialysis, Wilhelminenspital, 1160 Vienna, Austria
| | - Thomas Weichhart
- Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria.
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Sini S, Deepa D, Harikrishnan S, Jayakumari N. High-density lipoprotein from subjects with coronary artery disease promotes macrophage foam cell formation: role of scavenger receptor CD36 and ERK/MAPK signaling. Mol Cell Biochem 2016; 427:23-34. [PMID: 27995417 DOI: 10.1007/s11010-016-2895-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 12/02/2016] [Indexed: 12/25/2022]
Abstract
Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content. Using western blotting, we identified that piHDL profoundly upregulated the expression of scavenger receptor CD36 and suppressed the expression of ABCG1 and SRB1 in macrophages, thereby facilitating cholesterol influx capacity of macrophages. We then identified that CD36 did not act alone, indeed it was activated in macrophages along with ERK/MAPK, in response to piHDL, which in turn led to lipid accumulation as well as proinflammatory response via activation of NFkB and subsequent release of proinflammatory markers-TNF-ά and MMP-9. These effects were confirmed using pharmacological inhibitors for either CD36 or ERK/MAPK. Furthermore, piHDL treatment moderately activated PPAR-γ and Nrf2, the known regulators of CD36 in macrophages, suggesting that the two forms of HDL differentially regulate CD36 expression. Taken together, the results demonstrate that a novel CD36-ERK/MAPK-dependent mechanism is involved in macrophage lipid accumulation by piHDL, there by revealing the importance of functional deficiency in HDL and its potential link to atherogenesis.
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Affiliation(s)
- S Sini
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695011, India
| | - D Deepa
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695011, India
| | - S Harikrishnan
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695011, India
| | - N Jayakumari
- Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695011, India.
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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: 129] [Impact Index Per Article: 14.3] [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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49
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Abstract
Diabetes mellitus is associated with a considerably increased risk of premature atherosclerotic cardiovascular disease. Intensive glycemic control has essentially failed to significantly improve cardiovascular outcomes in clinical trials. Dyslipidemia is common in diabetes and there is strong evidence that cholesterol lowering improves cardiovascular outcomes, even in patients with apparently unremarkable lipid profiles. Here, the authors review the pathophysiology and implications of the alterations in lipoproteins observed in both type 1 and type 2 diabetes, the effect of medications commonly used in the management of diabetes on the lipid profile, the evidence for lifestyle and pharmaceutical interventions, and national and international recommendations for the management of dyslipidemia in patients with diabetes.
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Affiliation(s)
- Jonathan D Schofield
- Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK.
- University Department of Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
| | - Yifen Liu
- Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK
| | - Prasanna Rao-Balakrishna
- University Department of Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Rayaz A Malik
- Faculty of Medical and Human Sciences, Institute of Human Development, University of Manchester, Manchester, UK
- Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Handrean Soran
- University Department of Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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Yamashita S, Masuda D, Ohama T, Arai H, Bujo H, Kagimura T, Kita T, Matsuzaki M, Saito Y, Fukushima M, Matsuzawa Y. Rationale and Design of the PROSPECTIVE Trial: Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease. J Atheroscler Thromb 2016; 23:746-56. [PMID: 26803913 PMCID: PMC7399286 DOI: 10.5551/jat.32813] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/05/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Reduction of serum LDL-cholesterol by statins was shown to improve clinical outcomes in patients with coronary heart disease (CHD). Although intensive statin therapy significantly reduced cardiovascular risks, atherosclerotic cardiovascular events have not been completely prevented. Therefore, effective pharmacologic therapy is necessary to improve "residual risks" in combination with statins. Probucol has a potent antioxidative effect, inhibits the oxidation of LDL, and reduces xanthomas. Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Prior Coronary Heart Disease (PROSPECTIVE) is a multicenter, randomized, prospective study designed to test the hypothesis that the addition of probucol to other lipid-lowering drugs will prevent cerebro- and cardiovascular events in patients with prior coronary events and high LDL cholesterol levels. STUDY DESIGN The study will recruit approximately 860 patients with a prior CHD and dyslipidemia with LDL-C level ≥140 mg/dl without any medication and those treated with any lipid-lowering drugs with LDL-C level ≥100 mg/dl. Lipid-lowering agents are continuously administered during the study period in control group, and probucol (500 mg/day, 250 mg twice daily) is added to lipid-lowering therapy in the test group. The efficacy and safety of probucol with regard to the prevention of cerebro- and cardiovascular events and the intima-media thickness of carotid arteries as a surrogate marker will be evaluated. SUMMARY PROSPECTIVE will determine whether the addition of probucol to other lipid-lowering drugs improves cerebro- and cardiovascular outcomes in patients with prior coronary heart disease. Furthermore, the safety of a long-term treatment with probucol will be clarified.
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Affiliation(s)
- Shizuya Yamashita
- Department of Community Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Rinku General Medical Center, Izumisano, Osaka, Japan
| | - Daisaku Masuda
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tohru Ohama
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Dental Anesthesiology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan
| | - Hidenori Arai
- The National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Hideaki Bujo
- Department of Clinical Laboratory and Experimental Research Medicine, Toho University, Sakura Medical Center, Sakura, Chiba, Japan
| | - Tatsuo Kagimura
- Foundation for Biomedical Research and Innovation, Kobe, Hyogo, Japan
| | - Toru Kita
- Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan
| | | | - Yasushi Saito
- Chiba University Graduate School of Medicine, Chiba, Japan
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