| First Author | Raghavan S | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 27 | Pages | 10574-10589 |
| PubMed ID | 29777060 | Mgi Jnum | J:267098 |
| Mgi Id | MGI:6197333 | Doi | 10.1074/jbc.RA118.003491 |
| Citation | Raghavan S, et al. (2018) Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3-mediated degradation of the ABCA1 transporter. J Biol Chem 293(27):10574-10589 |
| abstractText | Although signaling of thrombin via its receptor protease-activated receptor 1 (Par1) is known to occur in atherothrombosis, its link to the actual pathogenesis of this condition is less clear. To better understand the role of thrombin-Par1 signaling in atherosclerosis, here we have studied their effects on cellular cholesterol efflux in mice. We found that by activating Par1 and cullin 3-mediated ubiquitination and degradation of ABC subfamily A member 1 (ABCA1), thrombin inhibits cholesterol efflux in both murine macrophages and smooth muscle cells. Moreover, disruption of the Par1 gene rescued ABCA1 from Western diet-induced ubiquitination and degradation and restored cholesterol efflux in apolipoprotein E-deficient (ApoE(-/-)) mice. Similarly, the Par1 deletion diminished diet-induced atherosclerotic lesions in the ApoE(-/-) mice. These observations for the first time indicate a role for thrombin-Par1 signaling in the pathogenesis of diet-induced atherosclerosis. We identify cullin 3 as a cullin-RING ubiquitin E3 ligase that mediates ABCA1 ubiquitination and degradation and thereby inhibits cholesterol efflux. Furthermore, compared with peripheral blood mononuclear cells (PBMCs) from ApoE(-/-) mice, the PBMCs from ApoE(-/-):Par1(-/-) mice exhibited decreased trafficking to inflamed arteries of Western diet-fed ApoE(-/-) mice. This finding suggested that besides inhibiting cholesterol efflux, thrombin-Par1 signaling also plays a role in the recruitment of leukocytes during diet-induced atherogenesis. Based on these findings, we conclude that thrombin-Par1 signaling appears to contribute to the pathogenesis of atherosclerosis by impairing cholesterol efflux from cells and by recruiting leukocytes to arteries. |
