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

Abstract

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. 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.

Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation

“…These findings indicate that an increase in fatty acid oxidation per se is not necessarily detrimental in the hypertrophied heart but that such an increase may play a central role in the maintenance of energetics in these animals. Our findings are consistent with a number of other recent studies that have reported associations between an increase in fatty acid oxidation and preserved LV function during hemodynamic overload ( 30 – 33 ). It should be noted, however, that the impact of increased fatty acid oxidation may be different in the setting of ischemia or diabetes.…”

Endothelial cell CD36 optimizes tissue fatty acid uptake

“…Both of these techniques assess the rapid accumulation of LCFAs and, for this reason, might have failed to show a defect in LCFA uptake into CM-Cd36 -/-hearts; CM CD36 is well established as a mediator of LCFA accumulation in cultured CMs (38,39) and as a provider of substrates required for the response to acute afterload (40). In addition, our studies highlight important differences in the contribution of ECs versus CMs to FA metabolism in the heart, and additional studies are needed to understand the mechanisms underlying these differences.…”

Adverse effects of Hif1a mutation and maternal diabetes on the offspring heart

“…7 ). Decreased myocardial levels of CD36 have been found detrimental, even in the absence of elevated circulating FAs, and to contribute to cardiac dysfunction [ 67 ]. The decreased Cd36 expression observed in the hearts of Hif1a + / − offspring of diabetic pregnancies is consistent with a previous report that Cd36 expression is regulated by HIF-1 [ 45 ].…”