Notoginsenoside R1 Protects Against High Glucose-Induced Cell Injury Through AMPK/Nrf2 and Downstream HO-1 Signaling

Abstract

Notoginsenoside R1 (NGR1), the primary bioactive compound found in Panax notoginseng, is believed to have antihypertrophic and antiapoptotic properties, and has long been used to prevent and treat cardiovascular diseases. However, its potential role in prevention of diabetic cardiomyopathy remains unclear. The present study aimed to investigate the mechanism of NGR1 action in high glucose-induced cell injury. H9c2 cardiomyocytes were cultured in a high-glucose medium as an in-vitro model, and apoptotic cells were visualized using TUNEL staining. Expression of Nrf2 and HO-1 was measured using Western blotting or reverse transcription-quantitative PCR (RT-qPCR). The Nrf2 small interfering (si) RNA was transfected into cardiomyocytes using Opti-MEM containing Lipofectamine® RNAiMAX. NGR1 protected H9c2 cardiomyocytes from cell death, apoptosis and hypertrophy induced by high glucose concentration. Expression of auricular natriuretic peptide and brain natriuretic peptide was remarkably reduced in NGR1-treated H9C2 cells. Western blot analysis showed that high glucose concentration markedly inhibited AMPK, Nrf2 and HO-1, and this could be reversed by NGR1 treatment. However, the cardioprotective effect of NGR1 was attenuated by compound C, which reverses Nrf2 and HO-1 expression levels, suggesting that AMPK upregulates Nrf2 and HO-1 gene expression, protein synthesis and secretion. Transfection of H9C2 cells with Nrf2 siRNA markedly reduced the cardioprotective effect of NGR1 via reduced expression of HO-1. These results indicated that NGR1 attenuated high glucose-induced cell injury via AMPK/Nrf2 signaling and its downstream target, the HO-1 pathway. We conclude that the cardioprotective effects of NGR1 result from upregulation of AMPK/Nrf2 signaling and HO-1 expression in cardiomyocytes. Our findings suggest that NGR1 treatment might provide a novel therapy for diabetic cardiomyopathy.

Duodenal-jejunal bypass surgery activates eNOS and enhances antioxidant system by activating AMPK pathway to improve oxidative stress diabetic cardiomyopathy

“…At the same time, we found that the myocardial AMPK pathway was significantly activated after DJB surgery, and many studies have shown that activation of the AMPK pathway is very important for the improvement of metabolism [32,33]. Similarly, activation of the AMPK pathway can promote eNOS phosphorylation and improve the antioxidant system [6,[34][35][36], suggesting that improvement of oxidative stress by DJB surgery may depend on the AMPK pathway. To verify the feasibility of the AMPK pathway on the phosphorylation levels of eNOS, SOD2, and NRF2/HO-1, we used an AMPK agonist to stimulate H9C2 cells in the HG+PA environment.…”

Notoginsenoside R1 Ameliorates Cardiac Lipotoxicity Through AMPK Signaling Pathway

“…NGR1 is one of the main active components in P. notoginseng and previous studies have shown that NGR1 could attenuate myocardial injury and reduce myocardial infarct size in an ischemia/reperfusion injury model ( Tong et al, 2019 ), which may be through Nrf2-HO-1 or mTOR induced inflammation and apoptosis signaling pathway ( Du et al, 2021 ; Liu et al, 2021 ). However, its mechanism on AMPK mediated lipotoxicity in AMI-post heart failure has not been described before.…”

Targeting the programmed cell death (PCD) signaling mechanism with natural substances for the treatment of diabetic cardiomyopathy (DCM)

“…Curcumin effectively alleviated oxidative stress, inhibited myocardial cell apoptosis, and improved cardiac remodeling and dysfunction in DCM. Du et al (2021) conducted an in vitro experiment to explore the protective effect of Notoginsenoside R1 (NGR1) against high glucose‐induced myocardial cell injury. The results showed that NGR1 reduced high glucose‐induced H9c2 myocardial cell death, apoptosis, and hypertrophy by upregulating the AMPK/Nrf2 signaling pathway and the expression of HO‐1.…”