Abstract
Laminar blood flow acts mainly on vascular endothelial cells(ECs) which modulates atheroprotective functions. ECs express laminar flow‐mediating molecules of the mechano‐sensor including G proteins, integrin, and growth factor receptor. However, flow‐mediated signaling pathway of G protein and GPCR is not well established. Recent studies have indicated that PAR‐1 Known as GPCR which involves cytoprotective and anti‐inflammatory responses in endothelial cells. Here, we addressed whether the PAR‐1 is involved by laminar flow‐mediated atheroprotective signaling. In present study, depletion of PAR‐1 with siRNA against human PAR‐1 inhibited flow‐mediated KLF2‐and Nrf2‐dependent gene expression in ECs. In addition, confocal analysis showed that PAR‐1 was internalized into early endosome in response to laminar flow suggesting that PAR‐1 is activated by laminar blood flow. We identified HDAC5 as a downstream target molecule of PAR‐1. Furthermore depletion of PAR‐1 reversed the flow‐mediated anti‐inflammatory response for TNFa‐induced VCAM‐1 expression and monocyte adhesiveness. Taken together, these results provide that flow‐induced PAR‐1 activation exerts atheroprotective signaling pathway in ECs.
Highlights
Atherosclerosis preferentially involves regions prone to low and/or disturbed blood flow at vessel branch points and the outer walls of bifurcations, and regions exposed to steady, high levels of laminar blood flow are relatively protected from atherosclerosis[1,2,3,4]
In the present study, we investigated whether protease-activated receptor-1 (PAR-1) acts as a mechano-sensor in the laminar flow-mediated atheroprotective signaling pathway
After cell had been exposed to laminar flow, ATAP2 binding affinity to surface PAR-1 was found to be significantly down-regulated in a time-dependent manner like as activated protein C (APC) which is an endogenous agonist of PAR-1 (Fig. 1C)
Summary
Atherosclerosis preferentially involves regions prone to low and/or disturbed blood flow at vessel branch points and the outer walls of bifurcations, and regions exposed to steady, high levels of laminar blood flow are relatively protected from atherosclerosis[1,2,3,4]. In a recently study, it was shown laminar flow-mediated signalings are negatively regulated by histone deacetylase 520 (HDAC5; a member of the class IIa histone deacetylases and negative regulator of myocyte enhancer factor-2 (MEF2), a downstream target of the laminar flow-induced ERK5 activating pathway)[21]. One study demonstrated that laminar flow reduced the cell surface expression of PAR-132, but the mechanism whereby PAR-1 acts as a mechano-sensor in the laminar flow-mediated atheroprotective signaling pathway has not been studied. We found that PAR-1 is activated by laminar flow and regulates laminar flow-induced atheroprotective gene expression dependent on Src, AMPK, ERK5, HDAC5 and eNOS in EC. We demonstrated that acetylcholine-induced vasorelaxation was diminished in aortic rings of PAR-1 KO compared to littermate controls These data provide evidence that PAR-1 is a mechano-sensor for laminar flow which mediates anti-atherosclerotic responses in EC
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