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Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter
Journal article   Open access   Peer reviewed

Protease-activated receptor 1 inhibits cholesterol efflux and promotes atherogenesis via cullin 3–mediated degradation of the ABCA1 transporter

Somasundaram Raghavan, Nikhlesh K. Singh, Arul M. Mani and Gadiparthi N. Rao
The Journal of biological chemistry, Vol.293(27), pp.10574-10589
07/06/2018
DOI: 10.1074/jbc.RA118.003491
PMCID: PMC6036195
PMID: 29777060
url
https://doi.org/10.1074/jbc.RA118.003491View
Published (Version of record) Open Access

Abstract

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.
 ABC transporter atherosclerosis cholesterol macrophage Signal Transduction

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