Xinkeshu formula restrains pathological cardiac hypertrophy through metabolic remodeling via AMPK/mTOR pathway

Xinkeshu (XKS) formula is a patented traditional Chinese medicine used to treat cardiovascular diseases for decades. However, little is known about its potential influence on heart metabolism under pathological conditions.

This study sought to explore the potential role of XKS in pathological cardiac hypertrophy, with a focus on metabolic remolding.

We established pathological cardiac models in mice by transverse aortic constriction (TAC) and isoprenaline (ISO) challenge with continuous oral administration of XKS at specified doses for 4 weeks. In cultured cardiomyocytes, we observed the effects on metabolism and the mechanisms that underlie the process.

In the TAC model mice, oral administration of XKS restrained cardiac hypertrophy, indicated by decreases in heart mass and cardiomyocyte size. Meanwhile, XKS also suppressed fetal gene induction and cardiac fibrotic response. Echocardiography examination showed that XKS improved heart contractility and diastolic function. Similar results were observed in the hearts of mice subjected to isoprenaline challenge. In cultured cardiomyocytes, angiotensin II stimulation induced cardiomyocytes enlargement and fetal gene induction, which were normalized by XKS. XKS reduced cellular energy charge to induce AMPK activation, which inactivated mTOR by modification of phosphorylation, contributing to attenuating cardiac hypertrophy. Following cardiac hypertrophy, metabolism was reprogrammed, whereas augmented glycolysis and mitochondrial oxidation were reduced by XKS. As result of mTOR suppression, XKS reduced HIF-1α accumulation and blocked HIF-1α nuclear translocation, and thus reduced angiogenesis by downregulating Vegf gene expression.

These results show that XKS modulated metabolic remodeling through the AMPK/mTOR cascade to restrain pathological cardiac hypertrophy. Our findings shed new light on the role of XKS in cardiac protection, particularly in the context of metabolic remodeling.