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NALP3 Inflammasome Activation in the Coronary Arterial Wall of Obese Mice

Inflammasomes as intracellular inflammatory machinery has been reported to switch on the inflammatory response to various danger signals. The present study hypothesized that activation of NALP3 inflammasomes turns on the endothelial inflammatory response and results in arterial endothelial dysfunction during the early stage of obesity and in response to adipokines. To test this hypothesis, we first observed increased inflammasomes activation in coronary arterial wall of obese mice, as shown by colocalization of NALP3 with apoptosis‐associated speck‐like protein (ASC) or caspase‐1 under confocal microscopy. The further studies in these obese mice found that plasma visfatin concentrations increased by 53.8% compared to normal mice. In addition, local transfection of visfatin shRNA in heart or daily injection of caspase‐1 inhibitor, WEHD (1 mg/kg/d) had no effects on visfatin level, but almost blocked obesity‐associated formation of NALP3 inflammasomes as shown by no co‐localization of NALP3 with ASC or caspase‐1. Correspondingly, IHC anlysis revealed that accumulation of T‐cells was abolished by visfatin shRNA and WEHD as shown by much less CD43 stains. In cultured mouse endothelial cells (ECs), confocal microscopy and size exclusion chromatography studies revealed that visfatin treatment significantly enhanced the NALP3 inflammasome complex formation and activation compared to control cells. Additionally visfatin treatment increased the caspase‐ 1 activity by 2.4 folds and IL‐1β production by 2.3 folds compared to control cells. ASC siRNA and WEHD substantially attenuated the visfatin‐induced caspase‐1 activity and IL‐1β production. In conclusion, the activation of NALP3 inflammasomes may be an important initiating mechanism responsible for the adipokine, visfatin to produce inflammatory response and endothelial dysfunction in coronary artery (supported by NIH grant HL057244, HL091464 and HL075316).