The Crosstalk between Cardiac Lipotoxicity and Mitochondrial Oxidative Stress in the Cardiac Alterations in Diet-Induced Obesity in Rats

Abstract

The impact of the mitochondria-targeted antioxidant MitoQ was evaluated in the cardiac alterations associated with obesity. Male Wistar rats were fed either a high fat diet (HFD, 35% fat) or a standard diet (CT, 3.5% fat) for 7 weeks and treated with MitoQ (200 µM). The effect of MitoQ (5 nM) in rat cardiac myoblasts treated for 24 h with palmitic acid (PA, 200 µM) was evaluated. MitoQ reduced cardiac oxidative stress and prevented the development of cardiac fibrosis, hypertrophy, myocardial 18-FDG uptake reduction, and mitochondrial lipid remodeling in HFD rats. It also ameliorated cardiac mitochondrial protein level changes observed in HFD: reductions in fumarate hydratase, complex I and II, as well as increases in mitofusin 1 (MFN1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and cyclophilin F (cycloF). In vitro, MitoQ prevented oxidative stress and ameliorated alterations in mitochondrial proteins observed in palmitic acid (PA)-stimulated cardiac myoblasts: increases in carnitine palmitoyltransferase 1A, cycloF, and cytochrome C. PA induced phosphorylation of extracellular signal-regulated kinases and nuclear factor-κB p65. Therefore, the data show the beneficial effects of MitoQ in the cardiac damage induced by obesity and suggests a crosstalk between lipotoxicity and mitochondrial oxidative stress in this damage

Oxidative Stress in Cardiovascular Diseases

“…Thus, the hydroxyl radical constitutes the most unstable radical ROS but with the strongest toxicity [5]. An increase in ROS production has already been described in several cardiac diseases such as myocardial fibrosis [29], type 2 diabetes [30,31], metabolic syndrome [32][33][34][35][36], cardiac hypertrophy [9,37,38], heart failure [39], and myocardial infarction [40,41].…”

“…Mitochondrial ROS production is also involved in many diabetes-related cardiovascular complications. Indeed, metabolic syndrome, characterized by diabetes and obesity, is associated with left ventricular hypertrophy and metabolic and diastolic dysfunction [34,36]. For example, mice fed with a high-fat high-sucrose diet develop mitochondrial oxidative stress (H 2 O 2 production), mitochondrial dysfunction (decreased ATP synthesis, complex II activity and mitochondrial respiration), and cardiac hypertrophy (increased wall thickness) [33,34].…”

Cells in Cardiovascular Disease: Using Diversity to Confront Adversity

“…The mingling of pathological mechanisms affecting cardiovascular health is clearly reflected by the risk of CVD associated with metabolic diseases, including conditions such as obesity or diabetes. This connection is explored in several studies of the present volume [ 5 , 15 ]. A link of these factors is studied by Actis-Dato et al in their study of the involvement of LRP-1 in insulin response in a myoblast cell line [ 23 ].…”

“…The role of oxidative stress in cardiac alterations associated to obesity is the subject of the study by Jiménez González et al [ 5 ]. The authors use a model of diet-induced obesity and myoblasts in culture to study the deleterious effects of high fat diet on cardiac function, and to show that antioxidants specifically targeted to mitochondria reduced cardiac oxidative stress and prevented cardiac damage.…”

“…The authors find that cultured human cardiac fibroblasts are targets of sST2, having a profibrotic effect that is prevented by NFkB inhibitors. The critical role played by cardiac fibroblasts in chronic heart disease is reflected in the number of studies of the volume that address their biological functions [ 5 , 7 , 9 , 10 , 11 ]. For instance, the study by Martin et al demonstrates that yet another mediator of inflammation, soluble phospholipase A2IIA (sPLA2-IIA), promotes myofibroblast differentiation and acts as a link between inflammation and fibrosis [ 9 ].…”