Gui Gan Shen Mai Yin attenuates cardiac hypertrophy and dysfunction in association with mitochondrial homeostasis and the PI3K/AKT1 signaling pathway

Abstract

This study aimed to evaluate the effects of Gui Gan Shen Mai Yin (GGSMY) on cardiac hypertrophy and dysfunction and to explore associated mechanisms. The chemical profile of the GGSMY aqueous extract was characterized using UPLC-MS. Candidate active ingredients and potential targets were analyzed by network pharmacology, and molecular docking was used to evaluate predicted interactions between representative components and AKT1. A mouse transverse aortic constriction (TAC) model was established, and mice received different doses of GGSMY for 4 weeks. Cardiac structure and function were assessed by echocardiography, while myocardial morphology and collagen deposition were evaluated using HE, WGA, and Masson staining. In primary neonatal rat cardiomyocytes stimulated with angiotensin II (Ang II), cell size was assessed by α-actinin immunofluorescence. The expression of hypertrophy-, fibrosis-, and inflammation-associated markers (BNP, MYH7, COL1A1, TGF-β, TNF-α, and IL-18) and AKT/p-AKT (Ser473) was measured by qRT-PCR and Western blotting. Oxidative stress and mitochondrial-related indices were assessed using ROS and MDA assays, JC-1, and MitoTracker Red. Network pharmacology identified 70 overlapping targets between GGSMY-associated targets and cardiac hypertrophy-associated targets, with the PI3K/AKT pathway emerging as a candidate regulatory axis. Molecular docking predicted potential interactions between several representative components and AKT1. In TAC mice, GGSMY attenuated the reductions in LVEF and fractional shortening and reduced cardiac hypertrophy, collagen deposition, and the expression of hypertrophy-, fibrosis-, and inflammation-associated markers. In Ang II-treated cardiomyocytes, GGSMY reduced cell enlargement and marker expression, attenuated mitochondrial membrane depolarization, increased MitoTracker Red fluorescence intensity and area-related readouts, and decreased ROS and MDA levels. GGSMY was also associated with lower p-PI3K/PI3K and p-AKT/AKT ratios, while SC79 partially counteracted selected GGSMY-associated effects. GGSMY attenuated pressure overload-induced cardiac hypertrophy and dysfunction, potentially through improved mitochondrial function-related changes, reduced oxidative stress, and modulation of PI3K/AKT signaling.