scholarly journals Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure

2017 ◽  
Vol 312 (3) ◽  
pp. H552-H560 ◽  
Author(s):  
Miranda M. Sung ◽  
Nikole J. Byrne ◽  
Ty T. Kim ◽  
Jody Levasseur ◽  
Grant Masson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Significant Proportion ◽  
Pressure Overload ◽  
Rapid Progression ◽  
Acid Uptake ◽  
Medium Chain ◽  
Energetic Stress

Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is presently unknown. To address this, we utilized a tamoxifen-inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood. Control mice (CD36 floxed/floxed mice) and icCD36KO mice were treated with tamoxifen and subsequently subjected to transverse aortic constriction (TAC) surgery to generate pressure overload-induced cardiac hypertrophy. Consistent with CD36 mediating a significant proportion of FA entry into the cardiomyocyte and subsequent FA utilization for ATP production, hearts from icCD36KO mice were metabolically inefficient and displayed signs of energetic stress, including activation of the energetic stress kinase, AMPK. In addition, impaired energetics in icCD36KO mice contributed to a rapid progression from compensated hypertrophy to heart failure. However, icCD36KO mice fed a medium-chain FA diet, whereby medium-chain FAs can enter into the cardiomyocyte independent from CD36, were protected from TAC-induced heart failure. Together these data suggest that limiting FA uptake and partial inhibition of FA oxidation in the heart via CD36 ablation may be detrimental for the compensated hypertrophic heart in the absence of sufficiently elevated circulating FAs to provide an adequate energy source. NEW & NOTEWORTHY Limiting CD36-mediated fatty acid uptake in the setting of obesity and/or insulin resistance protects the heart from cardiac hypertrophy and dysfunction. However, cardiomyocyte-specific CD36 ablation in the absence of elevated circulating fatty acid levels accelerates the progression of pressure overload-induced cardiac hypertrophy to systolic heart failure.

Sarcolemmal fatty acid uptake vs. mitochondrial β-oxidation as target to regress cardiac insulin resistanceThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 473-480 ◽  
Author(s):  
Joost J.F.P. Luiken
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Fatty Acid ◽  
Peer Review Process ◽  
Diabetic Patients ◽  
Central Feature ◽  
Acid Uptake ◽  
Cpt I ◽  
Rate Limiting

Cardiomyopathy and heart failure are frequent comorbid conditions in type-2 diabetic patients. However, it has become increasingly evident that insulin resistance, type-2 diabetes, and cardiomyopathy are not independent variables, and are linked through changes in metabolism. Specifically, elevated intracellular levels of long-chain fatty acid (LCFA) metabolites are a central feature in the development of cardiac insulin resistance, and their prolonged accumulation is an important cause of heart failure. In the insulin-resistant heart, the abundance of the LCFA transporters CD36 and FABPpm at the sarcolemma of cardiac myocytes appears to be markedly increased. Because circulating LCFA levels are increased in insulin resistance, the cardiac LCFA metabolizing machinery is confronted with drastic increases in substrate supply. Indeed, LCFA esterification into triacylglycerol and other lipid intermediates is increased, as is β-oxidation and reactive oxygen species production. Therapeutic strategies to normalize the cardiac LCFA flux would be most successful when the target is the rate-limiting step in cardiac LCFA utilization. Carnitine palmitoyltransferase (CPT)-I has long been considered to be this rate-limiting site and, accordingly, pharmacological inhibition of CPT-I, or β-oxidation enzymes, has been proposed as an insulin-resistance-antagonizing strategy. However, recent evidence indicates that, instead, sarcolemmal LCFA transport mediated by CD36 in concert with FABPpm provides a major site of flux control. In this review, it is proposed that a pharmacologically imposed net internalization of CD36 and FABPpm is the preferable strategy to limit LCFA entry and accumulation of LCFA metabolites, to regress cardiac insulin resistance and, eventually, prevent diabetic heart failure.

scholarly journals A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload

2009 ◽  
Vol 297 (5) ◽  
pp. H1585-H1593 ◽  
Author(s):  
David J. Chess ◽  
Ramzi J. Khairallah ◽  
Karen M. O'Shea ◽  
Wenhong Xu ◽  
William C. Stanley
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
High Fat Diet ◽  
Citrate Synthase ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Oxidative Enzymes ◽  
High Fat ◽  
Low Fat Diet

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice ( n = 10–12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (∼70%) and end-systolic and end-diastolic areas (∼100% and ∼45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

Dysfunctional Insulin Resistant/mTOR Activation Is Involved In The Formation of Pulmonary Hypertension In Pressure Overload-Induced Heart Failure

2021 ◽  
Author(s):  
Xiaojing Wu ◽  
Bo Dong ◽  
Tongxin Ni ◽  
Junhao Hu ◽  
Qi Zhou
Keyword(s):  
Heart Failure ◽  
Insulin Resistance ◽  
Pulmonary Hypertension ◽  
Cardiac Hypertrophy ◽  
Heart Function ◽  
Pressure Overload ◽  
Metabolic Changes ◽  
Heart Catheterization ◽  
Left Heart ◽  
Metabolic Pattern

Abstract Background: Heart failure (HF) usually presents with abnormal changes of metabolisms. Pulmonary hypertension (PH) is a frequent complication of left heart dysfunction. However, the association of serum metabolic changes with PH formation remains unknown. This study analyzed changes of serum metabolomic during the development of PH in a left heart pressure overload model. Methods: Male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) or sham surgery. Metabolomic analysis was performed on plasma samples of rats at 0 week, 3 weeks and 9 weeks after the surgery. Cardiac remodeling and heart function were determined by echocardiography. Right heart catheterization was performed to assay the mean pulmonary arterial pressure (mPAP). HE staining was performed to observe the remodeling of the myocardium and small pulmonary arteries.Results: The rats developed compensated cardiac hypertrophy with normal mPAP at 3 weeks and PH due to HF (PH-HF) at 9 weeks with distinct metabolic pattern after TAC. Twenty-five metabolites changed in the 9-week group compared with the 3-week group. KEGG analysis suggested abnormal insulin resistance and mTOR activation during the development of PH-HF. Acetylcarnitines related to insulin resistance increased about 3 folds from 4.14 ug/ml at 3 W group to 12.04μg/ml at 9-week group. L-leucine related to mTOR activation increased 1.6-fold with a VIP of 4.08 at 9 W when compared with that of the 3 W group.Conclusions: These results revealed distinct metabolic changes during the development of PH-HF. Dysfunctional insulin resistance and mTOR activation might be involved in the transition from compensated cardiac hypertrophy to PH-HF.

scholarly journals Endothelial Lipase Modulates Pressure Overload–Induced Heart Failure Through Alternative Pathway for Fatty Acid Uptake

Hypertension ◽  
2013 ◽  
Vol 61 (5) ◽  
pp. 1002-1007 ◽  
Author(s):  
Hideto Nakajima ◽  
Tatsuro Ishida ◽  
Seimi Satomi-Kobayashi ◽  
Kenta Mori ◽  
Tetsuya Hara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Alternative Pathway ◽  
Pressure Overload ◽  
Fatty Acid Uptake ◽  
Endothelial Lipase ◽  
Acid Uptake

Abstract 213: Fat Tissue specific Adipose Triglyceride Lipase as a major determinant for the development of pressure overload-induced heart failure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Janek Salatzki ◽  
Sarah Brix ◽  
Zsofia Ban ◽  
Daniela Fliegner ◽  
Verena Benz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Left Ventricular Mass ◽  
Pressure Overload ◽  
Tolerance Test ◽  
Left Ventricular ◽  
Adipose Triglyceride Lipase ◽  
Triglyceride Lipase

Introduction: Myocardial metabolism undergoes change in response to pathological cardiac hypertrophy (PH), characterized by increased reliance on glucose oxidation, decreased free fatty acid (FFA) oxidation and a loss of metabolic flexibility. Cardiac metabolism is influenced by other organs such as adipose tissue. Hence, we aimed to investigate the effect of Adipose Triglyceride Lipase (ATGL) in adipose tissue on the development of PH and heart failure (HF) in a pressure overload-induced cardiac hypertrophy model in mice. Methods: Male adipose tissue specific ATGL-knock out (atATGL-KO) and wild type mice (WT) underwent sham surgery (sham) or transverse aortic constriction (TAC). After 11 weeks, mice were sacrificed and organs were harvested. We performed echocardiography one week before and 11 weeks after surgery. Left ventricular mass (LVM), left ventricular mass/tibia length (LVM/TL) and ejection fraction (EF) were calculated. Beta-myosin heavy chain (β-MyHC) was measured in RNA of hearts. Insulin resistance was assessed by an intraperitoneal glucose tolerance test (GTT) and an insulin tolerance test (ITT). FFAs were measured in serum in total. Results: LVM and LVM/TL in WT was significantly higher compared to atATGL-KO after TAC (LVM/TL [mg/mm] WT-TAC: 18,0±2,2; atATGL-KO-TAC: 13,1±2,3; p<0,01). The higher increase of LVM in WT was associated with a larger left ventricle internal diameter. Reduction of EF was significantly more pronounced in WT compared to atATGL-KO ([%] WT: 28,81±6,9 atATGL-KO: 42,39±4,5; p<0,01). Beta-MyHC, a marker for PH, was markedly higher in WT-TAC than in atATGL-KO-TAC (WT-TAC: 11,3±3,6; atATGL-KO-TAC: 1.9±0,6; p<0,01). While WT-TAC showed higher Serum FFA-levels than atATGL-KO-TAC ([mmol/l] WT-TAC: 0,97±0,086; atATGL-KO-TAC: 0,49±0,032; p<0,001), GTT and ITT revealed a higher insulin sensitivity in atATGL-KO-TAC compared to WT-TAC. Conclusion: The present study demonstrates that atATGL is a crucial determinant for the development of pressure overload-induced PH and HI. The lack of ATGL in adipose tissue, the associated reduction of fatty acid release in the circulation and subsequent switches in cardiac energy substrates from free fatty acids to glucose are potential underlying mechanisms of this process.

scholarly journals Oxidative Stress as A Mechanism for Functional Alterations in Cardiac Hypertrophy and Heart Failure

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 931
Author(s):  
Anureet K. Shah ◽  
Sukhwinder K. Bhullar ◽  
Vijayan Elimban ◽  
Naranjan S. Dhalla
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Cardiac Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Hypertrophied Heart ◽  
Vasoactive Hormones

Although heart failure due to a wide variety of pathological stimuli including myocardial infarction, pressure overload and volume overload is associated with cardiac hypertrophy, the exact reasons for the transition of cardiac hypertrophy to heart failure are not well defined. Since circulating levels of several vasoactive hormones including catecholamines, angiotensin II, and endothelins are elevated under pathological conditions, it has been suggested that these vasoactive hormones may be involved in the development of both cardiac hypertrophy and heart failure. At initial stages of pathological stimuli, these hormones induce an increase in ventricular wall tension by acting through their respective receptor-mediated signal transduction systems and result in the development of cardiac hypertrophy. Some oxyradicals formed at initial stages are also involved in the redox-dependent activation of the hypertrophic process but these are rapidly removed by increased content of antioxidants in hypertrophied heart. In fact, cardiac hypertrophy is considered to be an adaptive process as it exhibits either normal or augmented cardiac function for maintaining cardiovascular homeostasis. However, exposure of a hypertrophied heart to elevated levels of circulating hormones due to pathological stimuli over a prolonged period results in cardiac dysfunction and development of heart failure involving a complex set of mechanisms. It has been demonstrated that different cardiovascular abnormalities such as functional hypoxia, metabolic derangements, uncoupling of mitochondrial electron transport, and inflammation produce oxidative stress in the hypertrophied failing hearts. In addition, oxidation of catecholamines by monoamine oxidase as well as NADPH oxidase activation by angiotensin II and endothelin promote the generation of oxidative stress during the prolonged period by these pathological stimuli. It is noteworthy that oxidative stress is known to activate metallomatrix proteases and degrade the extracellular matrix proteins for the induction of cardiac remodeling and heart dysfunction. Furthermore, oxidative stress has been shown to induce subcellular remodeling and Ca2+-handling abnormalities as well as loss of cardiomyocytes due to the development of apoptosis, necrosis, and fibrosis. These observations support the view that a low amount of oxyradical formation for a brief period may activate redox-sensitive mechanisms, which are associated with the development of cardiac hypertrophy. On the other hand, high levels of oxyradicals over a prolonged period may induce oxidative stress and cause Ca2+-handling defects as well as protease activation and thus play a critical role in the development of adverse cardiac remodeling and cardiac dysfunction as well as progression of heart failure.

Caprenin 1. Digestion, Absorption, and Rearrangement in Thoracic Duct-Cannulated Rats

1991 ◽  
Vol 10 (3) ◽  
pp. 325-340 ◽  
Author(s):  
D. R. Webb ◽  
R. A. Sanders
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Female Rats ◽  
Acid Uptake ◽  
Long Chain Fatty Acids ◽  
Male And Female ◽  
Medium Chain ◽  
Male And Female Rats ◽  
Long Chain ◽  
Chain Fatty Acids

Caprenin (CAP) is a triglyceride that primarily contains caprylic (C8:0), capric (C10:0), and behenic (C22:0) acids. This study was undertaken to determine whether or not CAP is qualitatively digested, absorbed, and rearranged like other dietary fats and oils that contain these medium-chain and very long-chain fatty acids. In vitro results showed that neat CAP, coconut oil (CO) and peanut oil (PO) were hydrolyzed by porcine pancreatic lipase. All of the neat triglycerides also were digested in vivo by both male and female rats. This was shown by the recovery of significantly more extractable lymphatic fat than with fat-free control animals and by the recovery of orally administered triglyceride-derived fatty acids in lymph triglycerides. However, substantially more PO (74%) and CO (51%) were recovered in lymph relative to CAP (10%). These quantitative differences are consistent with the fatty acid composition of each triglyceride and primary routes of fatty acid uptake. The 24-h lymphatic recovery of CAP-derived C8:0, C10:0, and C22:0 averaged 3.9%, 17.8%, and 11.2%, respectively, for male and female rats. The C8:0 and C10:0 results approximated those obtained with CO (2.0% and 16.3%, respectively). In contrast, the 24-h absorbability of C22:0 in CAP was significantly less than that seen in PO (55.4%). Finally, there was no evidence of significant rearrangement of the positions of fatty acids on glycerol during digestion and absorption. Those fatty acids recovered in lymphatic fat tended to occupy the same glyceride positions that they did in the neat administered oils. However, the lymph fats recovered from all animals dosed with fat emulsions were enriched with endogenous lymph fatty acids. It is concluded that CAP is qualitatively digested, absorbed, and processed like any dietary fat or oil that contains medium-chain and very long-chain fatty acids.

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