Abstract
Type 2 diabetes mellitus (T2DM) is a major health concern which may cause cardiovascular complications. Insulin resistance (IR), regarded as a hallmark of T2DM, is characterized by endothelial dysfunction. Ginsenoside Rc is one of the main protopanaxadiol-type saponins with relatively less research on it. Despite researches confirming the potent anti-inflammatory and antioxidant activities of ginsenoside Rc, the potential benefits of ginsenoside Rc against vascular complications have not been explored. In the present study, we investigated the effects of ginsenoside Rc on endothelial IR and endothelial dysfunction with its underlying mechanisms using high glucose- (HG-) cultured human umbilical vein endothelial cells (HUVECs) in vitro and a type 2 diabetic model of db/db mice in vivo. The results showed that ginsenoside Rc corrected the imbalance of vasomotor factors, reduced the production of Ang (angiotensin) II, and activated angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7)/Mas axis in HG-treated HUVECs. Besides, ginsenoside Rc improved the impaired insulin signaling pathway and repressed oxidative stress and inflammatory pathways which constitute key factors leading to IR. Interestingly, the effects of ginsenoside Rc on HG-induced HUVECs were abolished by the selective ACE2 inhibitor MLN-4760. Furthermore, ginsenoside Rc exhibited anti-inflammatory as well as antioxidant properties and ameliorated endothelial dysfunction via upregulation of ACE2 in db/db mice, which were confirmed by the application of MLN-4760. In conclusion, our findings reveal a novel action of ginsenoside Rc and demonstrate that ginsenoside Rc ameliorated endothelial IR and endothelial dysfunction, at least in part, via upregulation of ACE2 and holds promise for the treatment of diabetic vascular complications.
Highlights
Insulin resistance (IR) is usually defined as decreased sensitivity to metabolic actions of insulin in target tissues including muscle, liver, and adipose (Kim et al, 2006; Kong et al, 2019) and plays a critical role in the development of type 2 diabetes mellitus (T2DM), which is frequently present in obesity, dyslipidemia, and metabolic syndrome (DeFronzo and Ferrannini, 1991; Petersen et al., Ginsenoside Rc Ameliorates Endothelial IR2007)
As NO and ET-1 secreted by endothelium which is an important endocrinal organ are often considered the markers of endothelial IR (Kearney et al, 2008; Baratchi et al, 2017), we investigated the NO content in the culture medium and ET-1 mRNA
We evaluated the effects of ginsenoside Rc on high glucose- (HG-)induced reactive oxygen species (ROS) and proinflammatory factors
Summary
Insulin resistance (IR) is usually defined as decreased sensitivity to metabolic actions of insulin in target tissues including muscle, liver, and adipose (Kim et al, 2006; Kong et al, 2019) and plays a critical role in the development of type 2 diabetes mellitus (T2DM), which is frequently present in obesity, dyslipidemia, and metabolic syndrome (DeFronzo and Ferrannini, 1991; Petersen et al., Ginsenoside Rc Ameliorates Endothelial IR2007). Angiotensin (Ang) converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase which cleaves Ang II to generate Ang-(1–7) and is mainly expressed in vascular endothelial cells and the renal tubular epithelium (Donoghue et al, 2000; Tipnis et al, 2000). Ang-(1–7), the most important active product of ACE2 (Vickers et al, 2002; Jiang et al, 2014), interacts with its receptor Mas which is a G protein-coupled receptor to exert actions including vasodilation, antihypertrophy, antiinflammation, antioxidation, and improving vascular endothelial dysfunction (Santos et al, 2003; Rabelo et al, 2008; Gwathmey et al, 2010). Ang-(1–7) has been reported to improve endothelial dysfunction in db/db mice and Ang II-induced IR in endothelial cells (Tassone et al, 2013; Zhang et al, 2015), literature about ACE2/Ang-(1–7)/Mas axis emphasizing endothelial IR remains scarce
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