CASPASE‐1 ACTIVATION IS CRITICAL FOR ENDOTHELIAL ACTIVATION AND EARLY ATHEROGENESIS

Abstract

We hypothesized that caspase‐1(casp1)/inflammasome in endothelial cells (ECs) as the innermost cells exposed to circulation can sense hyperlipidemia as a danger signal in early atherosclerosis and initiate EC activation. Our data demonstrated that: 1) early hyperlipidemia induced casp‐1 expression and activation in mouse aorta in apolipoprotein E (ApoE)−/− mice with high fat (HF) diet; 2) proatherogenic oxidized low density lipoprotein(ox‐LDL), two oxLDL active components, such as lysophosphatidylcholine and lysophosphatidic acid, induced casp‐1 activation in human aortic ECs (HAECs); 3) deficiency of casp‐1 attenuated oxLDL‐induced EC activation by inhibiting the up‐regulation of EC adhesion molecules including ICAM‐1, VCAM‐1 and E‐selectin in both mRNA and protein levels in primary mouse aortic ECs; 4) casp‐1 inhibitors attenuated oxLDL‐induced HAEC activation and monocyte adhesion to HAECs. We then generated the ApoE−/−/Casp‐1−/− double knockout mice, and found that the double knockout mice contained significantly less atherosclerotic lesion in mouse aortic arch and less CD11b+/F4/80‐monocyte and CD11b+/F4/80+ monocyte recruitments into mouse aorta. Collectively, our data have demonstrated for the first time that caspase‐1/inflammasome in ECs can sense early hyperlipidemia and become activated, drive EC activation, and promote monocyte recruitment and early atherosclerosis.