Abstract 315: Caspase-1 Activation is Critical for Endothelial Cell Activation, Monocyte Recruitment, and Early Atherogenesis

Abstract

Activation of caspase-1(Casp-1), an inflammatory protease in a protein complex termed inflammasome, has been demonstrated to play an essential role in sensing environmental and metabolic danger signals and initiating inflammation. Our goal of this study is to examine a novel hypothesis that Casp-1 activation in endothelial cells (ECs) plays a critical role in promoting EC activation and accelerating early atherogenesis. We first found that hyperlipidemia induced casp-1 expression and activation in mouse aorta along with atherogenesis in apolipoprotein E (ApoE)-/- mice with high fat (HF) diet feeding. By generating the ApoE-/-/Casp-1-/- mice, we then found that the deficiency of Casp-1 in ApoE-/- background significantly attenuated early atherosclerotic lesion formation in mouse aortic sinus (42% reduction comparing to that ApoE-/- mice (n=9)) when fed with a HF diet for 3 weeks. Mechanistically, we found that the ApoE-/-/Casp-1-/- mice had significantly less CD11b+/F4/80- monocytes (0.2% vs 0.4% in ApoE-/- mice(n=10)) and CD11b+/F4/80+ macrophages (0.9% vs 1.8% in ApoE-/- mice) infiltration into mouse aorta after 3-week HF diet. Moreover, we found that there were less cytokine and chemokine expressions in the aorta of ApoE-/-/Casp-1-/- mice in comparison to that of ApoE-/- mice. Furthermore, the deficiency of Casp-1 attenuated hyperlipidemia-induced EC activation by inhibiting adhesion molecules including intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and E-selectin up-regulation both in mouse aorta and primary mouse aortic ECs. In in vitro experiments, we found that oxidized low density lipoprotein (ox-LDL) and two oxLDL active components, lysophosphatidylcholine and lysophosphatidic acid, induced Casp-1 activation through Reactive Oxygen Species pathway in human aortic ECs (HAECs). Finally, Casp-1 inhibitors attenuated oxLDL-induced monocyte adhesion to HAECs. Collectively, our data have demonstrated that Casp-1/inflammasome in ECs can sense hyperlipidemia and become activated, which drive EC activation and monocyte recruitment into aorta and promote early atherogenesis.