title: Involvement of calcium-sensing receptor in oxLDL-induced MMP-2 production in vascular smooth muscle cells via PI3K/Akt pathway.
abstract: Matrix metalloproteinase-2 (MMP-2) is constitutively expressed in vascular smooth muscle cells (VSMCs) and up-regulated in atherosclerotic lesion by various stimuli, such as oxidized low-density lipoprotein (oxLDL). Calcium-sensing receptor (CaSR) is also expressed in VSMCs, but it remains unclear whether CaSR is associated with overproduction of MMP-2 in VSMCs. In this study, the expression of MMP-2 was detected by real-time PCR and Western blot analysis, and the gelatinolytic activity of MMP-2 was measured using gelatin zymography. Our results showed that oxLDL enhanced MMP-2 expression and activity in rat aortic VSMCs in a time- and dose-dependent manner. In addition, CaSR expression was up-regulated by oxLDL. Manipulating CaSR function in these cells by NPS2390 (an antagonist of CaSR) or GdCl(3) (an agonist of CaSR) affected the oxLDL-induced MMP-2 production. In VSMCs, oxLDL stimulated the rapid activation of phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway, as determined by Western blot analysis. Phosphorylation of Akt and MMP-2 production stimulated by oxLDL were attenuated by LY294002 (a specific inhibitor of PI3K). Activation of Akt was suppressed by NPS2390 but enhanced by GdCl(3). In contrast, oxLDL had no stimulatory effect on the phosphorylation of JNK, and pretreatment with SP600125 (an inhibitor of JNK) produced no significant effect on oxLDL-induced MMP-2 production. These results suggest that CaSR mediates oxLDL-induced MMP-2 production in VSMCs via PI3K/Akt signal pathway.
authors.affiliation: Department of Pathophysiology, Harbin Medical University, Harbin, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Li
authors.forename: Fan-Juan
authors.initials: FJ
authors.lastname: Kong
authors.forename: Shu-Zhi
authors.initials: SZ
authors.lastname: Bai
authors.forename: Wen
authors.initials: W
authors.lastname: He
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Xing
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Xi
authors.forename: Guang-Wei
authors.initials: GW
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Guo
authors.forename: Hong-Zhu
authors.initials: HZ
authors.lastname: Li
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Wu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Guang-Dong
authors.initials: GD
authors.lastname: Yang
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Xu
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000218:Adamantane; D000873:Anthracenes; D002867:Chromones; D005682:Gadolinium; D048031:JNK Mitogen-Activated Protein Kinases; D008077:Lipoproteins, LDL; D020778:Matrix Metalloproteinase 2; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines; D044169:Receptors, Calcium-Sensing; C569355:2-quinoxaline-carboxamide-N-adamantan-1-yl; C099252:oxidized low density lipoprotein; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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