Abstract
Endothelial cell apoptosis plays an important role in the pathophysiological mechanism of vascular complications in type 2 diabetes mellitus (T2DM). Argirein, a new synthetic compound was demonstrated to inactivate NADPH oxidase to alleviate cardiac dysfunction in T2DM. Here, we investigated whether argirein medication attenuated the vascular dysfunction in T2DM by inhibiting endothelial cell apoptosis which was associated with NADPH oxidase. The rat aortic endothelial cells (RAECs) were incubated with glucose (30 mM) for 48 hour in vitro. It was shown that high glucose significantly increased the protein expression of BAX (Bcl-2 Associated X protein) and Caspase-3 and decreased Bcl2 (B-Cell Leukemia/Lymphoma 2) protein level in RAECs, which was normalized by argirein medication. The annexin V-FITC bound cell percentage and DNA fragments in agarose electrophoresis were markedly suppressed by argirein to confirm the anti-apoptotic property of argirein in RAECs. Furthermore, we found that argirein blocked the endothelin (ET)-1/Nox4 signal-dependent superoxide (O2−.) generation, which regulated endothelial cell apoptosis in RAECs. In vivo, argirein intervention relieved the vasodilatory response to acetylcholine and restored the expressions of Nox4 and BAX in the aorta endothelium of high-fat diet (HFD)-fed rats following streptozocin (STZ) injection. For the first time, we demonstrated that argirein could inhibit vascular endothelial cell apoptosis, which was attributed to blocking ET-1/Nox4 signal-dependent O2− generation in RAECs. This current study revealed the therapeutic effects of argirein to prevent the vascular complication in T2DM through inhibiting endothelial cell apoptosis which was associated with the anti-oxidative property of argirein.
Highlights
Type 2 diabetes mellitus (T2DM) affects a rapidly growing portion of the global population and is prone to an array of vascular complications[1]
We provided novel evidences that ET-1/Nox[4] signal-dependent O2−. generation was critical for suppressing the apoptosis of rat aortic endothelial cells (RAECs) triggered by high glucose
We demonstrated that type 2 diabetes mellitus (T2DM)-induced vascular dysfunction was alleviated by argirein intervention through inhibiting Nox4-associated endothelial apoptosis
Summary
Type 2 diabetes mellitus (T2DM) affects a rapidly growing portion of the global population and is prone to an array of vascular complications[1]. It was reported that argirein could substantially relieve isoproterenol-induced exacerbation of cardiac failure and alleviate cardiac dysfunction in T2DM, which was associated with suppressing NADPH oxidase activity[5,6]. Additional study from our group found that argirein blunt hepatosteatosis in diabetic rats fed with a HFD for 12 weeks combined with a single low dose of STZ, which was manifested as inhibiting DNA ladder and upregulated Bcl[2] and downregulated Bax in hepatocyte apoptosis[8]. We investigated whether argirein medication attenuated vascular lesion and dysfunction in T2DM rats by inhibiting endothelial cell apoptosis which was associated with the anti-oxidative property of argirein. Vascular dysfunction was produced in T2DM rats fed with HFD combined with low dose STZ administration[10]. Considering the effects of argirein on attenuating ET-1/NADPH oxidase signal in renal tissue and myocardium[5,13], we detected that the ET-1 system-dependent Nox4-dependent O2−. was involved in the improvement of apoptosis by argirein intervention
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