title: Angiotensin II induces an increase in MMP-2 expression in idiopathic ascending aortic aneurysm via AT1 receptor and JNK pathway.
abstract: The cellular and molecular mechanisms responsible for human idiopathic ascending aortic aneurysm (IAAA) remain unknown. Matrix metalloproteinase-2 (MMP-2) is a key enzyme for the degradation of extracellular matrix in aneurysmal walls. The aim of this study was to elucidate the role of the angiotensin II (Ang II) pathway in MMP-2 induction in IAAA aortic walls. Quantitative polymerase chain reaction and western blot analysis were used to compare the MMP-2 mRNA and protein levels in ascending aortic specimens with those in IAAA patients (n = 10) and heart transplant donors (n = 5) without any aortopathy. It was found that MMP-2 expression was significantly increased, which was associated with elastic lamellae disruption in IAAA walls. Additionally, the expression levels of angiotensinogen (AGT) and Ang II in the ascending aortic tissues from individuals with and without IAAAs were detected by western blot analysis and radioimmunoassay, respectively. The results demonstrated that the expressions of AGT and Ang II protein were significantly increased in the ascending aortic tissues of IAAA patients. Furthermore, whether Ang II induces MMP-2 expression was investigated using human IAAA walls ex vivo culture. It was found that exogenous Ang II increased the MMP-2 expression in a dose-dependent manner, which was completely inhibited by the Ang II type 1 receptor (AT1R) inhibitor candesartan and was mediated by c-Jun N-terminal kinase (JNK) activation. Taken together, these results indicate that Ang II can induce an increase of MMP-2 expression via AT1R and JNK in ex vivo cultured IAAA aortic walls, and suggest that angiotensin receptor blocker (ARB) drugs and JNK inhibitors have the potential in the prevention or treatment of IAAAs.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Aorta Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Chunmao
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Aorta Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China fwchangqian@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Aorta Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Aorta Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Aorta Surgery Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Sun
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D001011:Aorta / Q000201:enzymology*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2
keywords: angiotensin II; angiotensin II type 1 receptor; c-Jun NH2-terminal kinase; idiopathic ascending aortic aneurysm; matrix metalloproteinase-2