Neocryptotanshinone ameliorates insufficient energy production in heart failure by targeting retinoid X receptor alpha

Retinoid X receptor alpha (RXRa) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRa drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRa. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component-target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRa. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRa. Meanwhile, the critical downstream target genes of RXRa/PPARa, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRa. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRa/PPARa pathway in mice with HF post-AMI.

Automated summary

This study explored the pharmacological effects of NCTS on energy metabolism to protect against heart failure post-acute myocardial infarction (AMI) via RXRa. The results showed that NCTS protects the heart against ischaemic damage by activating RXRa and improving cardiac dysfunction and cellular hypoxic injury. NCTS also enhances fatty acid metabolism and mitochondrial biogenesis, promoting myocardial energy production.