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

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

So close, yet so far away: the relationship between MAM and cardiac disease

“…Additionally, it has been noted that the expression of MFN2 in the hearts of MS mice is significantly decreased compared to the control group. Altogether, these data suggest that obesity can disrupt communication between the ER and mitochondria ( 41 ). Furthermore, it has been reported that the deletion of FUNDC1 aggravates cardiac remodeling, mitochondrial dysfunction, and cell death in high-fat diet (HFD)-fed mice.…”

“…As obesity rates continue to rise, attention is increasingly focused on the associated myocardial injuries. Mice with metabolic syndrome (MS) induced by prolonged consumption of a Western diet often exhibit cardiac microvascular dysfunction, mitochondrial damage, and cardiac remodeling ( 41 ). The reshaping and deformation of mitochondria and the ER markedly reduce MAM size in MS mouse cardiomyocytes.…”

Mitochondria-associated endoplasmic reticulum membranes as a therapeutic target for cardiovascular diseases

“…Additionally, long-term consumption of diets high in fat and sucrose may cause abnormal lipid accumulation in both endothelial and myocardial cells in individuals with metabolic syndrome due to induced CAV1 expression. Lipid accumulation and lipotoxicity may have an impact on the destruction of MAMs and mitochondrial remodeling in cardiomyocytes, which could potentially lead to cardiomyocyte apoptosis, cardiac dysfunction, and remodeling ( Liu et al, 2023 ).…”

Expression of mRNA for molecules that regulate angiogenesis, endothelial cell survival, and vascular permeability is altered in endothelial cells isolated from db/db mouse hearts

“…Regulation of vascular permeability is also dependent on VEGF receptors but proceeds via a separate signaling pathway, namely via AKT and/or SRC activation (Simons et al 2016). EC dysfunction in MetS has been linked to oxidative stress and metabolic deregulation of ECs, which in turn affect vascular tone, permeability, angiogenesis, and surface molecule expression, and may subsequently trigger leukocyte adhesion, inflammation, and EC death (Liu et al 2023).…”