Pressure Overload Impairs Cardiac Function in Long-Chain Fatty Acid Transporter CD36-Knockout Mice

Abstract

CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown. The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed. By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation. These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.

The role of CD36 in cardiovascular disease

“…Comparatively, CD36 systemic knockout mice, when compared to wild-type mice, show pronounced myocardial interstitial fibrosis, cardiac enlargement, and contractile dysfunction after transverse aortic constriction (TAC) surgery. 158 The myocardium of CD36KO-TAC leads to insufficient energy supply not only due to the decrease of CD36 but also because of the increase of de novo amino acid synthesis from glucose, which further reduces the size of the high-energy phosphate pool. 159 However, whether overexpression of CD36 relieves the energy deficiency in pathological cardiac hypertrophy, and thereby stops the heart failure caused by cardiac pressure overload needs further investigation.…”

Metabolism in cardiomyopathy: every substrate matters

“…67 However, CD36 KO mice demonstrate increased cardiomyocyte hypertrophy and greater cardiac dysfunction after TAC. 68 Deletion of muscle specific isoform of carnitine palmityltransferase 1 (CPT-1b), the ratelimiting enzyme for the long-chain fatty acids entry into the mitochondria, is lethal. Heterozygous CPT-1b KO mice demonstrate normal cardiac function but when subject to pressure overload, exhibit exacerbated cardiac dysfunction and hypertrophy, accompanied by cardiac lipid accumulation and cardiomyocyte death.…”

Qiliqiangxin Capsules Optimize Cardiac Metabolism Flexibility in Rats With Heart Failure After Myocardial Infarction

“…FA is often discarded owing to its high oxygen consumption and potential lipotoxicity when modulating cardiac substrates in HF ( Heggermont et al, 2016 ). However, increasing glucose by irreversibly removing FA may not be possible ( He et al, 2012 ; Nakatani et al, 2013 ), and enhancing FA preference may be an alternative phenotype to restore cardiac energetics and function ( Kaimoto et al, 2017 ). Considering that FA produces approximately three times the ATP per molecule compared with glucose ( Peterzan et al, 2017 ), FA seems to be more efficient when oxygen is not limited in HF.…”