Puerarin inhibits NHE1 activity by interfering with the p38 pathway and attenuates mitochondrial damage induced by myocardial calcium overload in heart failure rats

Abstract

Previous studies have shown that puerarin plays a key role in protecting humans and animals from cardiovascular diseases. The exact mechanism of the therapeutic effect of puerarin on various cardiovascular diseases (protective effect on cardiomyocytes) is still unclear. In the present study, we identify the role of puerarin in an animal model of experimental heart failure (HF) and explore its underlying mechanisms. The HF rat model is induced by intraperitoneal injection of adriamycin (ADR), and puerarin is administered intragastrically at low, medium, and high concentrations. We demonstrate that puerarin significantly improves myocardial fibrosis and inflammatory infiltration and, as a result, improves cardiac function in ADR-induced HF rats. Mechanistically, we find for the first time that puerarin inhibits overactivated Na+/H+ exchange isoform 1 (NHE1) in HF, which may improve HF by decreasing Na+ and Ca2+ ion concentrations and attenuating mitochondrial damage caused by calcium overload; on the other hand, puerarin inhibits the activation of the p38 pathway in HF, reduces the expressions of TGF-β and proinflammatory cytokines, and suppresses myocardial fibrosis. In conclusion, our results suggest that Puerarin is an effective drug against HF and may play a protective role in the myocardium by inhibiting the activation of p38 and its downstream NHE1.

1. Introduction

Heart failure (HF), with high morbidity and mortality, is the outcome of many end-stage heart diseases that result in a heavy health burden [1,2]. Current HF therapy focuses on symptomatic treatment or delays the progression of the disease by reducing heart rate and cardiac preload and afterload [3]. Despite significant innovations in the medical treatment of HF in recent decades, its incidence continues to increase [4], making it worthwhile to understand the underlying pathological changes in HF and to find effective medicines.

The prevention and cure of HF with natural products are applicable and valuable research fields because plant sources are considered to be less toxic, with fewer side effects than synthetic medicines. Puerarin (Pue) is the main bioactive ingredient isolated from the root of the wild legume Pueraria lobata (wild) [5] and has been widely studied due to its multiple pharmacological effects. Emerging studies over the past few decades have demonstrated the efficacy of Pue in the prevention and treatment of cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy, cardiovascular complications of diabetes, myocardial infarction, and HF [6]. The therapeutic effects of Pue on a variety of cardiovascular diseases work through multiple targets and pathways. There is increasing evidence that Pue can modulate Na+[7], K+[8,9], and Ca2+[10] channels and regulate the concentration of these ions in cardiomyocytes to exert its anti-cardiac injury effects. However, studies of the effects of Pue on specific ion channels have been performed by using various channel inhibitors, not by directly recording ion currents, and other regulatory mechanisms for changes in the concentrations of these ions cannot be excluded.