title: Angiotensin II Induces an Increase in Matrix Metalloproteinase 2 Expression in Aortic Smooth Muscle Cells of Ascending Thoracic Aortic Aneurysms Through JNK, ERK1/2, and p38 MAPK Activation.
abstract: In this study, we hypothesized that angiotensin II (Ang II) induces matrix metalloproteinase 2 (MMP-2) upregulation in aneurysmal smooth muscle cells (ASMCs) derived from ascending thoracic aortic aneurysms (ATAAs). We compared MMP-2 protein levels in ascending aortic specimens using Western blot and plasma concentrations by enzyme-linked immunosorbent assay between ATAA (n = 40) and coronary heart disease patients (n = 40). Additionally, the protein level of angiotensinogen (AGT) in the ascending aorta and the plasma concentration of Ang II were detected by Western blot and radioimmunoassay, respectively, in ATAA and coronary heart disease patients. In ATAA patients, Ang II and MMP-2 plasma levels were significantly increased (P < 0.05). Additionally, AGT and MMP-2 protein levels in the aorta of ATAA patients were higher (P < 0.01). Enhanced AGT suggested that the amount of Ang II in aneurysmal aorta specimens may be also increased, which was confirmed by immunofluorescent staining for Ang II. Moreover, we investigated the effect of Ang II on MMP-2 upregulation by ASMCs and determined the Ang II receptors and intracellular signaling pathways that are involved. Our results showed that treatment with Ang II significantly increased the expression of MMP-2 through the Ang II type 1 receptor (AT1R) and activated the 3 major mitogen-activated protein kinases (MAPKs), JNK, ERK1/2, and p38 MAPK. In conclusion, these results indicate that Ang II can induce MMP-2 expression elevation through AT1R and MAPK pathways in ASMCs and suggest that there is therapeutic potential for angiotensin receptor blocker drugs and MAPK inhibitors in the prevention and treatment of ATAAs.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Department of Aorta Sugery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Chunmao
authors.initials: C
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Chang
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Sun
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Qian
authors.forename: Penghong
authors.initials: P
authors.lastname: Liu
authors.forename: Huawei
authors.initials: H
authors.lastname: Pei
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Guo
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017545:Aortic Aneurysm, Thoracic / Q000097:blood / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000804:Angiotensin II; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2