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

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.

Notoginsenoside R1 alleviates high glucose-evoked damage in RSC96 cells through down-regulation of miR-503

“…NGR1 is a phytoestrogen that is isolated from R. notoginseng. Recent studies have mentioned the potential of NGR1 in treating several complications of diabetes, like diabetic nephropathy [12], diabetic cardiomyopathy [13], and diabetic retinopathy [14]. However, the present paper for the first time evidenced NGR1 as a promising approach for DPN.…”

“…Because of that, NGR1 has been considered to have promise in treating various diseases, like chronic atrophic gastritis [9], cerebral hypoxia [10], Alzheimer's disease [11], and so forth. Of note, NGR1 is beneficial for several diabetes-related diseases, including diabetic nephropathy [12], diabetic cardiomyopathy [13] and diabetic retinopathy [14]. However, no studies have reported the function of NGR1 in treating DPN.…”

Notoginsenoside R1 protects boar sperm during liquid storage at 17°C

“…(2016) reported that NR1 protects against ischaemia/reperfusion injuries by regulating oxidative stress and increasing the activity of antioxidant enzymes in vitro. A previous study has shown that NR1 limits increases in ROS concentrations owing to its antioxidant capacity in vitro (Zhang et al., 2018). Therefore, we hypothesized that NR1 protected the plasma membrane and acrosome of boar spermatozoa by inhibiting ROS production.…”

“…Notoginsenoside R1 (NR1) is one of the main components of the Panax notoginseng rhizome (Meng, Sun, et al, 2014). The compound has been reported to promote oestrogen receptor alpha expression and activate antioxidant enzymes, which plays an important role in eliminating ROS (Zhang et al., 2018). NR1 also showed powerful antioxidant activity against ROS, both in vivo and in vitro.…”

<p>Focus on Notoginsenoside R1 in Metabolism and Prevention Against Human Diseases</p>

“…48 The protective effects of NG-R1 on advanced glycation end products (AGEs)-treated H9c2 cardiomyocytes and diabetic db/db mice have been investigated. Expectedly, NG-R1 significantly ameliorates AGEs-induced mitochondrial damage, decreases reactive oxygen species (ROS) production, and attenuates apoptosis by activating estrogen receptor α-dependent AKT and nuclear factor-erythroid 2-related factor 2 (NRF2) signaling pathways, leading to suppression of cardiac fibrosis and hypertrophy 49 (Figure 3).…”