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

• Published in: Biology direct Vol. 18; no. 1; pp. 9 - 16
• Main Authors: Liu, I.-Fan, Lin, Tzu-Chieh, Wang, Shu-Chi, Yen, Chia-Hung, Li, Chia-Yang, Kuo, Hsuan-Fu, Hsieh, Chong-Chao, Chang, Chia-Yuan, Chang, Chuang-Rung, Chen, Yung-Hsiang, Liu, Yu-Ru, Lee, Tsung-Ying, Huang, Chi-Yuan, Hsu, Chih-Hsin, Lin, Shing-Jong, Liu, Po-Len
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.03.2023; BioMed Central; BMC
• Subjects: Abdomen; Accumulation; Adipocytes; Analysis; Animals; Apoptosis; Autophagy; Brain damage; Brain injury; Brain natriuretic peptide; Cadherins; Cardiac mitochondria dysfunction; Cardiomyocytes; Cardiomyopathy; Cardiovascular diseases; Caspase; Caveolae; Caveolin; Caveolin 1 - genetics; Caveolin-1; Cells; Cholesterol; Development and progression; Diabetes; Diet; Diet, Western; Disruption; Echocardiography; Endoplasmic reticulum; Endothelial Cells; Endothelial dysfunction; Endothelium; Fatty acids; Heart; Heart Diseases; Heart failure; Hypertension; Immunohistochemistry; Insulin resistance; Lipid metabolism; Lipids; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - etiology; Metabolic syndrome X; Mice; Microvasculature; Mitochondria; Mitochondrial remodeling; Myocardium; Myocytes, Cardiac; Natriuretic peptides; Nitric oxide; Nitric-oxide synthase; Obesity; Oxidative stress; Permeability; Physiological aspects; Polymerase chain reaction; Proteins; Risk factors; Signal transduction; Sucrose; Transmission electron microscopy; Triglycerides; Ventricular Remodeling; Taiwan; Caveolin-1; Endothelial dysfunction; Mitochondrial remodeling; Caveolae; Metabolic syndrome; Cardiac mitochondria dysfunction
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-023-00363-z

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.