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Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure.

ABSTRACT: The energy metabolism of the failing heart is characterized by reduced fatty acid (FA) oxidation and an increase in glucose utilization. However, little is known about how energy metabolism-function relationship is relevant to pathophysiology of heart failure. Recent study showed that the genetic deletion of CD36 (CD36KO), which causes reduction in FA use with an increased reliance on glucose, accelerates the progression from compensated hypertrophy to heart failure. Here, we show the mechanisms by which CD36 deletion accelerates heart failure in response to pressure overload. CD36KO mice exhibited contractile dysfunction and death from heart failure with enhanced cardiac hypertrophy and interstitial fibrosis when they were subjected to transverse aortic constriction (TAC). The pool size in the TCA cycle and levels of high-energy phosphate were significantly reduced in CD36KO-TAC hearts despite an increase in glycolytic flux. De novo synthesis of non-essential amino acids was facilitated in CD36KO-TAC hearts, which could cause a further decline of the pool size. The ingestion of a diet enriched in medium-chain FA improved cardiac dysfunction in CD36KO-TAC hearts. These findings suggest that myocardial FA uptake through CD36 is indispensable for sufficient ATP production and for preventing an increased glycolytic flux-mediated structural remodeling during pressure overload-induced hypertrophy.

SUBMITTER: Umbarawan Y

PROVIDER: S-EPMC6089997 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure.

Umbarawan Yogi Y Syamsunarno Mas Rizky A A MRAA Koitabashi Norimichi N Obinata Hideru H Yamaguchi Aiko A Hanaoka Hirofumi H Hishiki Takako T Hayakawa Noriyo N Sano Motoaki M Sunaga Hiroaki H Matsui Hiroki H Tsushima Yoshito Y Suematsu Makoto M Kurabayashi Masahiko M Iso Tatsuya T

Scientific reports 20180813 1

The energy metabolism of the failing heart is characterized by reduced fatty acid (FA) oxidation and an increase in glucose utilization. However, little is known about how energy metabolism-function relationship is relevant to pathophysiology of heart failure. Recent study showed that the genetic deletion of CD36 (CD36KO), which causes reduction in FA use with an increased reliance on glucose, accelerates the progression from compensated hypertrophy to heart failure. Here, we show the mechanisms ...[more]

PMID: 30104639

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Project description:Introduction: The heart predominantly derives its energy from fatty acid (FA) oxidation. However, the uncoupling of lipid uptake and FA oxidation can result in abnormal cardiac lipid accumulation and lipotoxicity, particularly in the context of heart failure. CD36 is a critical mediator of FA uptake in cardiac tissue. Studies have shown that genetic deletion of CD36 can prevent the onset of cardiac hypertrophy and dysfunction in murine models of obesity and diabetes. Nevertheless, the precise role of CD36 knockdown or knockout in the development and progression of cardiac dysfunction under conditions of pressure overload remains unclear. Objective: This study aims to investigate the feasibility of CD36 partially knockdown in the prevention of cardiac lipotoxicity and functional impairment in pressure overload heart. Methods: Cardiac-specific CD36 totally knockout (CKO) and partially knockdown (CKD) mice were induced by genetics deletion and AAV-9 CD36 shRNA injection, respectively. Both CD36 CKO and CKD mice were subjected to transverse aortic constriction (TAC) operation to induce cardiac pressure overload. Cardiac function was measured by echocardiography. Cardiac lipid accumulation, FA oxidation and metabolic sate were also examined. Results: TAC operation induced significant cardiac dysfunction and pathological cardiac remodeling, accompanied by aberrant intra-myocardial lipid deposition and impaired FAO capacity. CD36 CKO attenuated aberrant lipid accumulation in the failing heart, while aggravated TAC-induced cardiac energy deprivation and oxidative stress. In contrast, CD36 CKD ameliorated TAC-induced lipid accumulation and excessive oxidative stress in the mice heart, accompanied by improved mitochondrial respiration function. Moreover, CD36 CKD induced a robust increase in glycolytic flux into the TCA cycle, which led to preserved ATP generation. As a result, CD36 CKD prevented the development of pressure overload-induced cardiac hypertrophy and dysfunction. Conclusion: In this study, we reported that CD36 CKD, not CD36 CKO, was able to protect against cardiac functional impairment in the pressure-overload heart. Manipulating CD36 was a feasible strategy to achieve an optimal point which maintain cardiac energy supply while avoiding lipotoxicity.

Dataset Information

Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure.

Publications

Myocardial fatty acid uptake through CD36 is indispensable for sufficient bioenergetic metabolism to prevent progression of pressure overload-induced heart failure.

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