Glucagon-Like Peptide-1 Protects Against Cardiac Microvascular Injury in Diabetes via a cAMP/PKA/Rho-Dependent Mechanism

Abstract

Impaired cardiac microvascular function contributes to cardiovascular complications in diabetes. Glucagon-like peptide-1 (GLP-1) exhibits potential cardioprotective properties in addition to its glucose-lowering effect. This study was designed to evaluate the impact of GLP-1 on cardiac microvascular injury in diabetes and the underlying mechanism involved. Experimental diabetes was induced using streptozotocin in rats. Cohorts of diabetic rats received a 12-week treatment of vildagliptin (dipeptidyl peptidase-4 inhibitor) or exenatide (GLP-1 analog). Experimental diabetes attenuated cardiac function, glucose uptake, and microvascular barrier function, which were significantly improved by vildagliptin or exenatide treatment. Cardiac microvascular endothelial cells (CMECs) were isolated and cultured in normal or high glucose medium with or without GLP-1. GLP-1 decreased high-glucose–induced reactive oxygen species production and apoptotic index, as well as the levels of NADPH oxidase such as p47phox and gp91phox. Furthermore, cAMP/PKA (cAMP-dependent protein kinase activity) was increased and Rho-expression was decreased in high-glucose–induced CMECs after GLP-1 treatment. In conclusion, GLP-1 could protect the cardiac microvessels against oxidative stress, apoptosis, and the resultant microvascular barrier dysfunction in diabetes, which may contribute to the improvement of cardiac function and cardiac glucose metabolism in diabetes. The protective effects of GLP-1 are dependent on downstream inhibition of Rho through a cAMP/PKA-mediated pathway.

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Both hyperglycemia and dyslipidemia impair heart function in diabetes. To exclude the hypoglycemic capacity when we assessed the cardioprotective effects of Ex‐4 and saxagliptin, we used a 1.5 U/day insulin treatment as a control, as previously reported (Wang et al., 2013). As expected, insulin treatment had the same effects on blood glucose, glucose tolerance, and body weight as exendin‐4 and saxagliptin in DM (Figure 1b–d).…”

“…Previous studies have reported that in diabetes, Ex‐4 suppressed downstream from Rho via a cAMP/protein kinase A (PKA)‐mediated pathway (Wang et al., 2013). We established that Ex‐4 inhibited diabetes‐related activation of Rho kinase and PPARα in vivo and in vitro.…”

“…Some studies have attributed the benefits of Ex‐4 on DCM to its effects on infiltrating macrophages, cardiac microvascular injury, and mitochondrial dysfunction (Tate et al., 2016; Wang et al., 2013; Wassef et al., 2017). However, the present study mainly focused on the effects of GLP‐1 on lipid regulation because, along with hyperglycemia, lipid accumulation and toxicity play key roles in DCM (Kusminski et al., 2009; Yang et al., 2007).…”

“…Our previous study demonstrated that the RhoA/Rock pathway is strongly activated in patients with diabetes (Liu et al., 2016). Moreover, there is evidence that the RhoA/ROCK pathway contributes to DM pathogenesis both in vitro and in vivo (Furukawa et al., 2005; Wang et al., 2013). GLP‐1 may attenuate the oxidative stress induced in cardiac microvascular endothelial cells by high glucose via the activation of cAMP/PKA and the inhibition of downstream ROCK activity (Wang et al., 2013).…”

“…GLP‐1R agonists and DPP‐4 inhibitors have beneficial effects on the cardiovascular system (Ban et al., 2008; Noyan‐Ashraf et al., 2009; Timmers et al., 2009). Previous studies have shown that GLP‐1 and its analogs protected the heart against ischemia‐reperfusion injury and diabetes mellitus (Tate, Robinson, Green, McDermott & Grieve, 2016; Wang et al., 2013). They also protected isolated CMs from oxidative damage (Chang et al., 2013) and high‐glucose stress (Younce, Burmeister & Ayala, 2013).…”