A novel mechanism of diabetic vascular endothelial dysfunction: Hypoadiponectinemia-induced NLRP3 inflammasome activation

Abstract

It has been well documented that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. However, the exact molecular mechanism which mediates this process has not been fully described. The current study aimed to investigate the role of hypoadiponectinemia-induced NLRP3 inflammasome activation in diabetic vascular endothelial dysfunction and its molecular mechanism. Male adult adiponectin knockout mice and wild type mice were fed with a high fat diet to establish a type 2 diabetic mellitus model. In addition, human umbilical vein endothelial cells (HUVECs) were cultured and subjected to high glucose/high fat (HG/HF). The NLRP3 inflammasome activation was increased in type 2 diabetic mice and treatment of diabetic aortic segments with MCC950, a potent selective inhibitor of NLRP3 inflammasome ex vivo improved endothelial-dependent vasorelaxation. NLRP3 inflammasome activation and vascular endothelial injury were significantly increased in APN-KO mice compared with WT mice in diabetes and MCC950 decreased diabetic vascular endothelial dysfunction to comparable levels in APN-KO mice and WT mice. Adiponectin could decrease NLRP3 inflammasome activation and attenuate endothelial cell injury, which was abolished by NLRP3 inflammasome overexpression. Inhibition of peroxynitrite formation preferentially attenuated NLRP3 inflammasome activation in APN-KO diabetic mice. The current study demonstrated for the first time that hypoadiponectinemia-induced NLRP3 inflammasome activation was a novel mechanism of diabetic vascular endothelial dysfunction.

High circulating follistatin-like protein 1 as a biomarker of a metabolically unhealthy state

“…Thus, it is conceivable that FSTL1 levels may not only reflect the MU state, but may also activate the NLRP3 inflammasome in macrophages infiltrating VAT, thereby resulting in an MU state with more adverse inflammatory profiles as mediators of increasing metabolic risk. Furthermore, low levels of adiponectin from adipocyte showing the FSTL1 as a marker of metabolic unhealth inverse correlation with the cardiovascular disease [30] also induced activation of the NLRP3 inflammasome [31,32]. Taken altogether, these findings indicate that additional investigations to identify the relationships between adiponectin and FSTL1 are necessary.…”

The opposite effects of nitric oxide donor, S‐nitrosoglutathione, on myocardial ischaemia/reperfusion injury in diabetic and non‐diabetic mice

“…We and others reported the increased superoxide anion production, lipid peroxidation, and NADPH oxidase activity in the plasma and tissue of type 2 diabetic mice . It is well established that oxidative stress is involved in the development and progression of diabetes mellitus and diabetic complications.…”

Anthocyanins increase serum adiponectin in newly diagnosed diabetes but not in prediabetes: a randomized controlled trial

“…The study of our laboratory also found that anthocyanin protected against diabetes-related endothelial dysfunction [16]. On the other hand, hypoadiponectinemia-induced in ammasome activation may be the molecular mechanism for diabetic vascular endothelial dysfunction [19]. Basic and clinical studies have identi ed the anti-atherogenic function of adiponectin [20] and its positive effect on vascular in ammation and endothelial function [21].…”