title: SIRT1 attenuates PAF-induced MMP-2 production via down-regulation of PAF receptor expression in vascular smooth muscle cells.
abstract: Silent mating type information regulation 2 homolog 1 (SIRT1) is known as a key regulator in the protection of various vascular disorders, however, no direct evidences have been reported in the progression of atherosclerosis. Considering the pivotal role of matrix metalloproteinase-2 (MMP-2) in plaque destabilization, this study investigated the role of SIRT1 on MMP-2 production in vascular smooth muscle cells (VSMCs) induced by platelet activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine). In VSMCs stimulated with resveratrol, SIRT1 activator, PAF receptor (PAFR) was internalized and then its protein levels were diminished. It was attenuated in cells pretreated with proteasome or lysosome inhibitor. Also, the degradation of PAFR in SIRT1-stimulated cells was significantly attenuated by β-arrestin2 depletion. In cells treated with nicotinamide, SIRT1 deacetylase inhibitor, PAFR internalization by resveratrol or reSIRT1 was inhibited, demonstrating that deacetylation of SIRT1 is an important step in SIRT1-induced PAFR down-regulation. Moreover, PAF-induced MMP-2 production in VSMCs and aorta was attenuated by resveratrol. In the aorta of SIRT1 transgenic mice, the PAF-induced MMP-2 expression was prominently attenuated compared to that in wild type mice. Taken together, it was suggested that SIRT1 down-regulated PAFR in VSMCs via β-arrestin2-mediated internalization and degradation, leading to an inhibition of PAF-induced MMP-2 production.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Yun H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Jin U
authors.initials: JU
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.
authors.forename: So Y
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea. Electronic address: chidkim@pusan.ac.kr.
authors.forename: Chi D
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1 / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D002352:Carrier Proteins; C561966:PAF protein, mouse; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C039351:platelet activating factor receptor; D020778:Matrix Metalloproteinase 2; D046988:Proteasome Endopeptidase Complex; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Deacetylation; GPCR; MMP-2; PAFR; SIRT1; β-Arrestin2