Early Hyperlipidemia Promotes Endothelial Activation via a Caspase-1-Sirtuin 1 Pathway

Abstract

Objective The role of receptors for endogenous metabolic danger signals-associated molecular patterns (DAMPs) has been characterized recently as bridging innate immune sensory systems for DAMPs to initiation of inflammation in bone marrow-derived cells such as macrophages. However, it remains unknown whether endothelial cells (ECs), the cell type with the largest numbers and the first vessel cell type exposed to circulating DAMPs in the blood, can sense hyperlipidemia. This report determined whether caspase-1 plays a role in ECs in sensing hyperlipidemia and promoting EC activation. Approach and Results Using biochemical, immunological, pathological and bone marrow transplantation methods together with the generation of new apoplipoprotein E (ApoE)−/−/caspase-1−/− double knock-out mice we made the following observations: 1) early hyperlipidemia induced caspase-1 activation in ApoE−/− mouse aorta; 2) caspase-1−/−/ApoE−/− mice attenuated early atherosclerosis; 3) caspase-1−/−/ApoE−/− mice had decreased aortic expression of pro-inflammatory cytokines and attenuated aortic monocyte recruitment; and 4) caspase-1−/−/ApoE−/− mice had decreased EC activation including reduced adhesion molecule expression and cytokine secretion. Mechanistically, oxidized lipids activated caspase-1 and promoted pyroptosis in ECs by a ROS mechanism. Caspase-1 inhibition resulted in accumulation of sirtuin 1 (Sirt1) in the ApoE−/− aorta, and Sirt1 inhibited caspase-1 upregulated genes via activator protein-1 (AP-1) pathway. Conclusions Our results demonstrate for the first time that early hyperlipidemia promotes EC activation before monocyte recruitment via a caspase-1-Sirt1-AP-1 pathway, which provides an important insight into the development of novel therapeutics for blocking caspase-1 activation as early intervention of metabolic cardiovascular diseases and inflammations.

Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis

“…Moreover, the smaller HAECs have higher pyroptosis rates than larger HAECs after stimulation with proatherogenic lipids. The activation of caspase-1 after stimulation with proatherogenic lipids promotes ECs activation as judged by increased intercellular adhesion molecule-1 expression in HAECs as we demonstrated previously (9). Our results show that the inhibition of VEGFR-2 increases caspase-1 activation in HAECs induced by LPC treatment and that the activation of caspase-1 inhibits VEGFR-2 expression in HAECs.…”

“…Of note, our previous studies only reported the effect of oxLDL in activating caspase-1 in HAECs. Here, we found the new results on the effects of other proatherogenic lipids in promoting caspase-1 activation (9). Taken together, the results demonstrated that proatherogenic lipids induce caspase-1 activation in HAECs, which may promote EC activation in a larger size of cells and inflammatory cell death in a smaller size of cells.…”

“…It has been reported that dyslipidemia attenuates EC proliferation in vitro and angiogenesis in vivo (14 -16). Although the role of caspase-1 in the dyslipidemic environment and atherogenesis remains controversial (31), the dominant concept supported by our own report (9) is that caspase-1 plays a proatherogenic role, which is supported by results collected from apoE Ϫ/Ϫ /caspase-1 Ϫ/Ϫ mice (9,32,33) (33) studied the role of caspase-1 deficiency in full-blown atherosclerosis in apoE Ϫ/Ϫ mice after high fat feeding for 8 weeks (32) and 12 weeks (33). The differences of endothelial cell sizes were observed previously (37,38).…”

“…D, bar graphs show the quantitation data of VEGFR-2 expressions. *, p Ͻ 0.05. strate of caspase-1, suggesting that caspase-1 activation in early atherogenesis promotes endothelial activation via a Sirt1 degradation pathway (9). To determine whether activation of Sirt1 has the same effect as inhibition of caspase-1 in promoting VEGFR-2 expression, we performed the same experiment as previous ones using Sirt1 activator pretreatment in LPCtreated HAECs.…”

“…in early atherosclerosis the caspase-1-inflammasome pathway in ECs can sense elevated lipids as endogenous metabolic danger signal-associated molecular patterns (DAMPs) and activate ECs (9,10). ECs that line the inner surface of the vessel wall are the first cells exposed to metabolite-related endogenous danger signals in the circulatory system (1).…”