A defined multi-metabolite formulation derived from Salvia miltiorrhiza alleviates obesity-associated cardiac lipotoxicity via modulating mitochondrial dynamics.

BACKGROUND

Obesity is a major risk factor for lipotoxic cardiomyopathy, a process involving lipid metabolism disorders, inflammatory responses, and mitochondrial dysfunction. Salvia miltiorrhiza (Danshen), a traditional Chinese medicinal plant, contains water-soluble metabolites with multitarget regulatory potential. Although some monomers of S. miltiorrhiza have been proved to be effective in cardiovascular diseases, the combined effects of metabolites and the mechanism remains unclear. This study aimed to investigate the cardioprotective effects and potential mechanisms of SABP, a defined formulation of four metabolites derived from S. miltiorrhiza (danshensu, salvianolic acid A, salvianolic acid B, and protocatechuic aldehyde), against lipotoxic myocardial injury, with a focus on the regulation of mitochondrial dynamics.

METHODS

A palmitic acid (PA)-induced lipotoxicity model in H9c2 cardiomyocytes and a high-fat diet (HFD)-induced obesity model in ApoE -/- mice were established. In vitro, the effects of SABP on cell viability (CCK-8), mitochondrial membrane potential (JC-1), mitochondrial dynamics-related proteins (Drp1, Fis1, Mfn2, Opa1), and apoptosis-related proteins (cleaved caspase-3, caspase-3) were assessed. In vivo evaluations involved fat distribution (Micro-CT), cardiac function (echocardiography), cardiac structure (HE, Masson staining, and TEM), serum lipid levels, inflammatory factors, cardiac enzyme activity (ELISA), and protein expression analysis in cardiac tissue (Western blot).

RESULTS

In vitro results showed that SABP significantly improved PA-induced reductions in cell viability and mitochondrial membrane potential, downregulated Drp1 and Fis1, upregulated Opa1 and Mfn2, and decreased the cleaved caspase-3/caspase-3 ratio. In vivo, SABP intervention reduced heart weight index and heart-tibia ratio, improved left ventricular systolic function, decreased fat accumulation and serum lipid abnormalities, attenuated inflammatory cytokine and myocardial enzyme levels, alleviated myocardial structural damage and fibrosis, and restored mitochondrial morphology. Western blot findings in cardiac tissue were consistent with in vitro results.

CONCLUSION

SABP may protect against cardiac lipotoxic injury by improving lipid metabolism, reducing inflammation, and restoring mitochondrial dynamics homeostasis, highlighting its potential as a multi-component herbal therapy for metabolic cardiomyopathy and providing experimental support for the development of such plant-derived therapeutics targeting this disease.