Jin-Xin-Kang alleviates heart failure by mitigating mitochondrial dysfunction through the Calcineurin/Dynamin-Related Protein 1 signaling pathway

Abstract

Ethnopharmacological relevance: Chronic heart failure (CHF) is a severe consequence of cardiovascular disease, marked by cardiac dysfunction. Jin-Xin-Kang (JXK) is a traditional Chinese herbal formula used for the treatment of CHF. This formula consists of seven medicinal herbs, including Ginseng (Ginseng quinquefolium (L.) Alph.Wood), Astragali Radix (Astragalus membranaceus (Fisch.) Bunge), Salvia miltiorrhiza (Salvia miltiorrhiza Bunge), Descurainiae Semen Lepidii Semen (Descurainia sophia (L.) Webb ex Prantl), Leonuri Herba (Leonurus japonicus Houtt.), Cinnamomi Ramulus (Cinnamomum cassia (L.) J.Presl), and Ilex pubescens (Ilex pubescens Hook. & Arn.). Its clinical efficacy has been validated through prospective randomized controlled studies. However, the specific mechanisms of action for this formula have yet to be elucidated.

Aim of the study: This study aimed to investigate the effect of JXK on mitochondrial function and its mechanism in the treatment of CHF.

Methods: JXK components were qualitatively analyzed using UPLC-Q-Orbitrap-MS. HF was induced in mice via transverse aortic constriction (TAC). After successful model establishment, lyophilized JXK-L (4.38 g/kg) and JXK-H (13.14 g/kg) were administered for 8 weeks. In vitro, hypertrophic myocardium was induced using angiotensin II (Ang II) for 48 h, followed by JXK-L and JXK-H treatment. Network pharmacology and molecular docking techniques were used to predict the relevant targets of JXK. Cardiac function, serum markers, and histopathological changes were evaluated to assess cardiac function. Immunofluorescence of Tomm20, mitochondrial membrane potential, and ROS were measured to assess mitochondrial dysfunction. Protein expression of calcineurin (CaN) and Drp1 in the myocardium was assessed by Western blot analysis.

Results: We detected that the active components of JXK include terpenes, glycosides, flavonoids, amino acids, and alkaloids, among others. In mice with CHF, JXK improved cardiac function and reversed ventricular remodeling. Network pharmacology indicated that JXK can inhibit the calcium signaling pathway. The molecular docking results demonstrated that the active components of JXK effectively bind with CaN. Both in vitro and in vivo experiments confirmed that JXK regulated the CaN/Drp1 pathway and alleviated mitochondrial dysfunction.

Conclusion: JXK can inhibit the CaN/Drp1 pathway to improve mitochondrial function, and consequently treat CHF.

Keywords: CaN/Drp1 pathway; Chronic heart failure; Jin-Xin-Kang; Mitochondrial dysfunction.