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Several studies on chronic systolic heart failure (HF) have demonstrated that body mass index is inversely associated with mortality, the so-called obesity paradox, but the mechanisms are not entirely clear. Our aim is to investigate to the role of fatty acids metabolism and its underlying mechanism in development of HF.
The model of HF was produced by transverse aortic constriction (TAC) in C57 mice (6 weeks old). High fat diet (HFD) or normal diet (ND) was fed for 8 weeks. AAV9 was used for myocardium-specific overexpression of CD36.
Treatment with high fat diet (HFD, 45% energy as fat) for 8 weeks improved cardiac function and restored cardiac hypertrophy in TAC mice. Specifically, treatment with high fat diet increased mitochondrial fusion and the ratio of L-OPA1/S-OPA1 which were decreased in TAC mice. CD36 overexpression exerted similar effects as treatment with HFD. Mechanistically, fatty acid utilization increased the expression of Yme1l which regulates the processing of OPA1, resulting in the elevation of the L-OPA1/S-OPA1 ratio and the resultant mitochondrial fusion.
These results suggested that increasing fatty acid metabolism in myocardium improves cardiac function through OPA1-mediated restoration of mitochondrial dynamics in pressure overload-induced HF via upregulation of Yme1l.