High mobility group box protein 1 as a novel vascular permeability factor derived from endothelial inflammasome activation during obesity (688.5)

Abstract

The early onset of type II diabetes in obese individuals is characteristic of increased vascular permeability leading to diabetic vasculopathy. However, it remains unknown how obesity instigates endothelial dysfunction resulting in vascular hyperpermeability. Here, we tested a hypothesis that visfatin, an injurious adipokine activates endothelial Nlrp3 inflammsome to produce high mobility group box protein 1 (HMGB1) and that HMGB1 serves as a novel vascular permeability factor to mediate the onset of obesity‐associated vascular hyperpermeability. In coronary arteries of Nlrp3+/+ mice fed high fat diet (HFD) for 6 weeks, confocal microscopic analysis showed significantly lower expression of gap junction proteins (GJPs) including VE‐Cadherin, ZO‐2 and occludin in the coronary arterial endothelium compared to mice on normal diet (ND). In vivo assessment of vascular integrity demonstrated that more Evans blue was extravasated into the myocardium in mice on HFD compared to mice on ND. However, such HFD‐induced decrease in endothelial GJP level and increase in vascular permeability were significantly attenuated in Nlrp3‐/‐ mice. Accompanied with these vascular permeability alterations, interestingly, HMGB1 expression was elevated in coronary arterial endothelium of HFD‐treated Nlrp3+/+ mice, but not in Nlrp3‐/‐ mice. In cultured mouse microvascular endothelial cells (MVECs), visfatin markedly decreased expression of GJPs and increased endothelial permeability. These visfatin‐induced changes in GJPs and endothelial permeability were blocked when MVECs were treated with HMGB1 inhibitor glycyrrhizin, caspase‐1 inhibitor WEHD or siRNA targeting HMGB1 receptor RAGE, respectively. Together, these data suggest that during obesity Nlrp3 inflammasome is activated due to the action of increased adipokines such as visfatin, which produces HMGB1 to serve as a vacular permeability factor leading to the onset of diabetic vasculopathy and ultimately resulting in atherosclerosis.Grant Funding Source: Supported by NIH grants HL057244, HL091464 and HL075316