Cardiac Metabolic Alterations in Hypertensive Obese Pigs

OCL, 2015

The aim of our study was to know whether high dietary energy intake (HDEI) with equilibrated and unbalanced diets in term of lipid composition modify the fatty acid profile of cardiac phospholipids and function of various cardiac cells and to know if the changes in membrane lipid composition can explain the modifications of cellular activity. Wistar rats were fed either a control or high-fat (HF) diet for 12 weeks and Zucker diabetic fatty (ZDF) rats as well as their lean littermate (ZL) a control diet between week 7 to 11 of their life. Energy intake and abdominal obesity was increased in HF-fed and ZDF rats. Circulating lipids were also augmented in both strains although hyperglycemia was noticed only in ZDF rats. HDEI induced a decrease in linoleate and increase in arachidonate in membrane phospholipids which was more pronounced in the ZDF rats compared to the HF-fed rats. In vivo cardiac function (CF) was improved in HF-fed rats whereas ex vivo cardiac function was unchanged, suggesting that environmental factors such as catecholamines stimulated the in vivo CF. The unchanged ex vivo CF was associated with an increased cardiac mass which indicated development of fibrosis and/or hypertrophy. The increased in vivo CF was sustained by an augmented coronary reserve which was related to the cyclooxygenase pathway and accumulation of arachidonate in membrane phospholipids. In conclusion, before triggering a diabetic cardiomyopathy, HDEI stimulated the CF. The development of cardiomyopathy seems to result from fibrosis and/or hypertrophy which augments myocardial stiffness and decreases contractility. Keywords: High dietary energy intake / abdominal adiposity / myocardial function / phospholipid composition / arachidonic acid / coronary reserve Résumé-Évolution du stade de l'activation mécanique jusqu'à la cardiomyopathie chez le rat rendu obèse par des régimes équilibré en graisses ou riche en acides gras saturés et mono-insaturés. Notre objectif a été de savoir si l'excès calorique (EC) modifie la composition en acides gras des phospholipides et la fonction cardiaques et si ces modifications des membranes expliquent les changements d'activité des cellules cardiaques. Des rats Wistar ont été nourris soit avec un régime contrôle, soit avec un régime riche en graisse (RRG) pendant 12 semaines et des rats Zucker diabétiques gras (ZDF) ainsi que leurs homologues maigres (ZL) avec un régime contrôle entre leur 7 e et 11 e semaine de vie. L'ingestion calorique et l'obésité abdominale ont été augmentées chez les rats RRG et ZDF. Une hyperlipidémie a été observée dans les 2 souches, mais l'hyperglycémie n'a été observée que chez les animaux ZDF. L'EC a provoqué une diminution en linoléate et une augmentation en arachidonate dans les membranes cardiaques qui a été plus prononcée chez les rats ZDF. La fonction cardiaque (FC) in vivo a été plus élevée chez les rats RRG malgré une FC ex vivo inchangée. Les catécholamines circulantes pourraient expliquer les discordances. La stabilité de la FC ex vivo a été associée à une augmentation de la masse cardiaque suggérant le développement d'une fibrose et/ou d'une hypertrophie. L'augmentation de la FC in vivo a été soutenue par un

Journal of the American Heart Association, 2016

Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH-induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury. After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin conten...

Acta veterinaria, 2006

Cardiovascular diseases are often associated with energy deficit and in many cases this is also accompanied by lipid disorders such as hyperlipidemias and obesity. The aim of the study was to check mitochondrial oxidative capacity in the course of twelve weeks atherogenic hypercholesterolic diet. Thirty five Chinchilla rabbits, male, were randomized to one of two groups: a control group (A, n=17) received (per os) physiological saline; experimental group (B, n=18) received atherogenic 2% hypercholesterolemic diet. Isolation of the mitochondrial fraction of the heart was done by the method of Tyler. The oxygen consumption rate was studied in different respiration phases: as basal, unstimulated (V 4) and as ADP-stimulated (V 3), and expressed as indices: respiratory control ratio (RCR) and ADP/O. Hypercholesterolemic atherogenic diet induced profound perturbations in mitochondrial energy metabolism and oxidative capacity. Basal oxygen consumption rate without ADP (V 4) and the maximal ADP-stimulated respiration rate (V 3) showed a marked reduction (quantitative changes); sensibility of mitochondria to ADP (ADP/O) was also reduced (qualitative change) in rabbits treated by atherogenic diet (group B) compared to controls (group A). Respiratory control ratio was not significantly different among the groups. These results indicate that hypercholesterolemic atherogenic diet impairs mitochondrial oxidative capacity without affecting coupling of oxidative and phosphorilative processes.

The Journal of Nutritional Biochemistry, 2014

Nutritional transition has contributed to growing obesity, mainly by changing eating habits of the population. The mechanisms by which diet-induced obesity leads to cardiac injury are not completely understood, but it is known that obesity is associated to impaired cardiac function and energy metabolism, increasing morbidity and mortality. Therefore, our study aimed to investigate the mechanisms underlying cardiac metabolism impairment related to Western diet-induced obesity. After weaning, male Swiss mice were fed a Western diet for 16 weeks in order to induce obesity. After this period, the content of proteins involved in heart energy metabolism GLUT1, cytosolic lysate and plasma membrane GLUT4, AMPK, pAMPK, IRβ, IRS-1, PGC-1α, CPT1 and UCP2 was evaluated. Also, the oxidative phosphorylation of myocardial fibers was measured by high-resolution respirometry. Mice in the Western diet group (WG) presented altered biometric parameters compared to those in control group, including higher body weight, increased myocardial lipid deposition and glucose intolerance, which demonstrate the obesogenic role of Western diet. WG presented increased CPT1 and UCP2 contents and decreased IRS-1, plasma membrane GLUT4 and PGC-1α contents. In addition, WG presented cardiac mitochondrial dysfunction and reduced biogenesis, demonstrating a lower capacity of carbohydrates and fatty acid oxidation and also decreased coupling between oxidative phosphorylation and adenosine triphosphate synthesis. Cardiac metabolism impairment related to Western diet-induced obesity is probably due to damaged myocardial oxidative capacity, reduced mitochondrial biogenesis and mitochondria uncoupling, which compromise the bioenergetic metabolism of heart.

Biochimica Et Biophysica Acta - Molecular And Cell Biology Of Lipids, 2019

Involvement of pericardial adipose tissue in cardiac fibrosis of dietary-induced obese minipigs-Role of mitochondrial function, BBA-Molecular and Cell Biology of Lipids,

Journal of Molecular Medicine, 2010

The metabolic syndrome is a constellation of metabolic disorders including obesity, hypertension, and insulin resistance, components which are risk factors for the development of diabetes, hypertension, cardiovascular, and renal disease. Pathophysiological abnormalities that contribute to the development of the metabolic syndrome include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities. Recent evidence suggests that impaired myocardial mitochondrial biogenesis, fatty acid metabolism, and antioxidant defense mechanisms lead to diminished cardiac substrate flexibility, decreased cardiac energetic efficiency, and diastolic dysfunction. In addition, enhanced activation of the renin-angiotensinaldosterone system and associated increases in oxidative stress can lead to mitochondrial apoptosis and degradation, altered bioenergetics, and accumulation of lipids in the heart. In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging, and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction. These mitochondrial abnormalities can predispose a metabolic cardiomyopathy characterized by diastolic dysfunction. Mitochondrial dysfunction and resulting lipid accumulation in skeletal muscle, liver, and pancreas also impede insulin metabolic signaling and glucose

Diabetes, 2007

OBJECTIVE-In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVO 2) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS-Oxygen consumption and cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H 2 O 2 generation determined in isolated mitochondria. RESULTS-db/db hearts exhibited reduced cardiac function and increased MVO 2. Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H 2 O 2 production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 ␣-subunit of ATP synthase was reduced. CONCLUSIONS-These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from ␤-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.

Obesity, 2009

nature publishing group intervention and Prevention IntroductIon The complications of obesity are frequently associated with BMI, percentage of body fat, and changes in fat distribution (1,2). However, variables other than the traditional body composition and lipid profile may be further improving the discrimination of obesity effects, mainly on cardiac health. Energy and nutrient balances can be assessed by the combination of indirect calorimetry with dietary control. A major advantage of this approach is that changes in body nutrient stores and cardiac metabolic shifting can be detected well before they could be measured with available techniques for assessing risk factors for cardiac disease (3). Cardiac damage represents one of the main health problems associated with obesity-induced morbidity and mortality (1), but the mechanisms that are triggered for this obesity-related disease are not completely clear. Cardiac muscle utilizes a variety of substrate to produce energy and the heart can shift from one substrate to another depending on food intake (4). As the use of oxygen is vital for oxidative phosphorylation, representing a major intracellular source of reactive oxygen species (ROS), changes in diet compounds, or substrate for energy generation may result in higher ROS, thus inducing oxidative stress, an imbalance between oxidant and antioxidant systems in favor of the former (3,5). This concept may be regarded as a paradox because metabolic function is strictly dependent on oxygen delivery and use, and intact mitochondria are necessary for energy production. However, ROS generated in mitochondrial respiratory chain

Circulation, 2014

Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycat...

Acta Physiologica

Obesity-induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA-induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes. K E Y W O R D S diabetes, heart, lipotoxicity, mitochondria This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.