Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor α and Its Downstream Signaling.

Bin Zhang,Chenyang Zhang,Shihuan Kuang,Guibo Sun,Xuelian Zhang,Xiaobo Sun,Jingxue Ye,Jingyi Zhang

doi:10.3389/fphar.2018.01227

Abstract

Diabetic cardiomyopathy (DCM) leads to heart failure and death in diabetic patients, no effective treatment is available. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and our previous studies have showed cardioprotective and neuroprotective effects of NGR1. However, its role in protecting against DCM remains unexplored. Herein, we examine potential effects of NGR1 on cardiac function of diabetic db/db mice and H9c2 cardiomyocytes treated by advanced glycation end products (AGEs). In vitro experiments revealed that pretreatment with NGR1 significantly decreased AGEs-induced mitochondria injury, limited an increase in ROS, and reduced apoptosis in H9c2 cells. NGR1 eliminated ROS by promoting estrogen receptor α expression, which subsequently activated Akt and Nrf2-mediated anti-oxidant enzymes. In vivo investigation demonstrated that NGR1 significantly reduced serum lipid levels, insulin resistance, the expression of enzymes related to cardiomyopathy, and the expression of apoptotic proteins. Finally, NGR1 improved cardiac dysfunction and attenuated histological abnormalities, as evidenced by elevating ejection fraction and fractional shortening, and reducing cardiac fibrosis. Mechanistically, NGR1 promoted ERα expression, which led to the activation of Akt-Nrf2 signaling and the inhibition of the TGFβ pathway. Collectively, these results strongly indicate that NGR1 exerts cardioprotective effects against DCM through its inhibition of oxidative stress and apoptosis, and eventually suppresses cardiac fibrosis and hypertrophy, which suggests that NGR1 is a potential therapeutic medicine for the treatment of DCM.

Highlights

Diabetic complications have become a more severe threat to human health in recent years
To investigate the protective effects of Notoginsenoside R1 (NGR1) on advanced glycation end products (AGEs)-induced H9c2 cardiomyocyte death, we initially evaluated the general toxicity of AGEs
Consistent with the Transferase-Mediated dUTP Nick End Labeling (TUNEL) assay results, annexin V/PI staining and quantitative analysis by flow cytometry showed that AGEs treatment significantly increased apoptosis in H9c2 cells by almost 4.25-fold compared with the control, NGR1 preconditioning markedly reduced this increase to three-fold change (P < 0.01, Figures 3C,D)

Summary

Introduction

Diabetic complications have become a more severe threat to human health in recent years. Cardiovascular complications, including diabetic cardiomyopathy (DCM), account for approximately 80% of diabetic deaths (Amos et al, 1997). Accumulating research has demonstrated underlying disease mechanisms that include oxidative stress, inflammation, mitochondrial dysfunction, and lipotoxicity; each potentially contributing to the pathophysiology of DCM (Cai et al, 2006; Kuwabara et al, 2015; Cheng X. et al, 2016; Vulesevic et al, 2016). Substantial progress has been made in the investigation of DCM in recent years, the underlying molecular mechanisms of DCM are still not fully understood.

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