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Protective effects of acarbose against vascular endothelial dysfunction through inhibiting Nox4/NLRP3 inflammasome
Xiao-Xue Li1, Sun-Kai Ling1, Ming-Yue Hu1
1Department of Pathology and Pathophysiology, Southeast University School of Medicine, Nanjing, 210009, China.
Abstract:
The cardiovascular efficacy of glucose-lowering drugs is needed due to the cardiovascular complication in type 2 diabetes mellitus (T2DM). Acarbose is an α-glucosidase inhibitor that suppresses postprandial hyperglycemia, however, the cardiovascular protection of acarbose has still remained controversial. NLRP3 inflammasome activation mediated tight junction disruption, a hallmark event of endothelial barrier dysfunction leading to endothelial hyperpermeability in diabetes. Given the anti-inflammatory property of acarbose, it was investigated that acarbose protected against vascular endothelial barrier dysfunction through inhibiting NLRP3 inflammasome in vascular endothelial cells in T2DM rats. The rat aortic endothelial cells (RAECs) were incubated with high glucose (HG, 30 mM) for 24 h in vitro. It was found that HG significantly induced the formation and activation of NLRP3 inflammasome, which was markedly blocked by acarbose treatment. Furthermore, acarbose blocked the Nox4-dependent superoxide (O2.-) generation, which regulated NLRP3 inflammasome in RAECs. Importantly, we found that acarbose remarkably enhanced the junction protein expression of ZO-1 and VE-Cadherin and consequently abolished vascular hyperpermeability, which was associated with inhibiting NLRP3 inflammasome in RAECs. In vivo, acarbose intervention relieved vascular leakage in the heart of diabetic rats injected with Evans blue dye and the vasodilatory response to acetylcholine, which was accompanied with the restoration of ZO-1, VE-Cadherin, Nox4 and NLRP3 inflammasome in the aortal endothelium of diabetic rats. Taken together, our data indicated that acarbose ameliorated endothelial barrier dysfunction by directly inhibiting NLRP3 inflammasome which was dependent on inhibiting Nox4 oxidase-dependent O2.- production. These properties might carry a potential significance for acarbose in cardiovascular protection in diabetic patients.
Insights
Acarbose protects against vascular endothelial barrier dysfunction in type 2 diabetes by inhibiting the NLRP3 inflammasome and Nox4-dependent superoxide production, potentially offering cardiovascular protection.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Pharmacology
Background:
- Cardiovascular complications are a major concern in type 2 diabetes mellitus (T2DM).
- Endothelial barrier dysfunction, characterized by tight junction disruption and hyperpermeability, contributes to cardiovascular issues in diabetes.
- The role of NLRP3 inflammasome activation in diabetes-induced endothelial dysfunction is increasingly recognized.
Purpose of the Study:
- To investigate the potential of acarbose, an alpha-glucosidase inhibitor, in protecting against vascular endothelial barrier dysfunction in T2DM.
- To elucidate the underlying mechanisms, focusing on the inhibition of NLRP3 inflammasome and its dependence on Nox4 oxidase.
Main Methods:
- In vitro studies using rat aortic endothelial cells (RAECs) exposed to high glucose (HG).
- Assessment of NLRP3 inflammasome activation, superoxide production (Nox4-dependent), and expression of junction proteins (ZO-1, VE-Cadherin).
- In vivo studies in T2DM rats involving vascular leakage assessment (Evans blue) and acetylcholine-induced vasodilation.
Main Results:
- High glucose induced NLRP3 inflammasome activation and endothelial hyperpermeability in RAECs.
- Acarbose treatment markedly blocked HG-induced NLRP3 inflammasome activation and superoxide generation.
- Acarbose enhanced ZO-1 and VE-Cadherin expression, abolishing vascular hyperpermeability in vitro.
- In vivo, acarbose reduced vascular leakage and improved vasodilatory response in diabetic rats, accompanied by normalized ZO-1, VE-Cadherin, Nox4, and NLRP3 inflammasome levels.
Conclusions:
- Acarbose ameliorates endothelial barrier dysfunction in T2DM by directly inhibiting the NLRP3 inflammasome.
- This protective effect is dependent on the inhibition of Nox4 oxidase-dependent superoxide production.
- Acarbose demonstrates potential cardiovascular protective properties in diabetic patients through its anti-inflammatory and endothelial-protective mechanisms.
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