Long-term administration of Western diet induced metabolic syndrome in mice and causes cardiac microvascular dysfunction, cardiomyocyte mitochondrial damage, and cardiac remodeling involving caveolae and caveolin-1 expression

Springer Science and Business Media LLC - 2023
I.-Fan Liu1,2, Tzu-Chieh Lin3,4, Shu-Chi Wang5, Chia-Hung Yen6, Chia-Yang Li7, Hsuan-Fu Kuo8,3,7,9, Chong-Chao Hsieh10,11,4, Chia-Yuan Chang12, Chuang-Rung Chang13,14, Yung-Hsiang Chen15,16, Yu-Ru Liu17, Tsung-Ying Lee17, Chi-Yuan Huang17, Chih-Hsin Hsu18, Shing-Jong Lin19,1,20,21,2, Po-Len Liu17,22,23
1Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
2Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan
3Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
5Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
6Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
7Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
8Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
9Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
10Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
11Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
12Department of Mechanical Engineering, National Cheng Kung University, Tainan, Taiwan
13Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
14Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan
15Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
16Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
17Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
18Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
19Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
20Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
21Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
22Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
23Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

Tóm tắt

Long-term consumption of an excessive fat and sucrose diet (Western diet, WD) has been considered a risk factor for metabolic syndrome (MS) and cardiovascular disease. Caveolae and caveolin-1 (CAV-1) proteins are involved in lipid transport and metabolism. However, studies investigating CAV-1 expression, cardiac remodeling, and dysfunction caused by MS, are limited. This study aimed to investigate the correlation between the expression of CAV-1 and abnormal lipid accumulation in the endothelium and myocardium in WD-induced MS, and the occurrence of myocardial microvascular endothelial cell dysfunction, myocardial mitochondrial remodeling, and damage effects on cardiac remodeling and cardiac function. We employed a long-term (7 months) WD feeding mouse model to measure the effect of MS on caveolae/vesiculo-vacuolar organelle (VVO) formation, lipid deposition, and endothelial cell dysfunction in cardiac microvascular using a transmission electron microscopy (TEM) assay. CAV-1 and endothelial nitric oxide synthase (eNOS) expression and interaction were evaluated using real-time polymerase chain reaction, Western blot, and immunostaining. Cardiac mitochondrial shape transition and damage, mitochondria-associated endoplasmic reticulum membrane (MAM) disruption, cardiac function change, caspase-mediated apoptosis pathway activation, and cardiac remodeling were examined using TEM, echocardiography, immunohistochemistry, and Western blot assay. Our study demonstrated that long-term WD feeding caused obesity and MS in mice. In mice, MS increased caveolae and VVO formation in the microvascular system and enhanced CAV-1 and lipid droplet binding affinity. In addition, MS caused a significant decrease in eNOS expression, vascular endothelial cadherin, and β-catenin interactions in cardiac microvascular endothelial cells, accompanied by impaired vascular integrity. MS-induced endothelial dysfunction caused massive lipid accumulation in the cardiomyocytes, leading to MAM disruption, mitochondrial shape transition, and damage. MS promoted brain natriuretic peptide expression and activated the caspase-dependent apoptosis pathway, leading to cardiac dysfunction in mice. MS resulted in cardiac dysfunction, remodeling by regulating caveolae and CAV-1 expression, and endothelial dysfunction. Lipid accumulation and lipotoxicity caused MAM disruption and mitochondrial remodeling in cardiomyocytes, leading to cardiomyocyte apoptosis and cardiac dysfunction and remodeling.

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