title: Angiotensin II increases matrix metalloproteinase 2 expression in human aortic smooth muscle cells via AT1R and ERK1/2.
abstract: Increased levels of angiotensin II (Ang II) and activated matrix metalloproteinase 2 (MMP-2) produced by human aortic smooth muscle cells (human ASMCs) have recently been implicated in the pathogenesis of thoracic aortic aneurysm (TAA). Additionally, angiotensin II type 1 receptor (AT1R)-mediated extracellular signal-regulated kinase (ERK)1/2 activation contributes to TAA development in Marfan Syndrome. However, there is scant data regarding the relationship between Ang II and MMP-2 expression in human ASMCs. Therefore, we investigated the effect of Ang II on MMP-2 expression in human ASMCs and used Western blotting to identify the Ang II receptors and intracellular signaling pathways involved. Reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence data demonstrated that Ang II receptors were expressed on human ASMCs. Additionally, Ang II increased the expression of Ang II type 2 receptor (AT2R) but not AT1R at both the transcriptional and translational levels. Furthermore, Western blotting showed that Ang II increased MMP-2 expression in human ASMCs in a dose- and time-dependent manner. This response was completely inhibited by the AT1R inhibitor candesartan but not by the AT2R blocker PD123319. In addition, Ang II-induced upregulation of MMP-2 was mediated by the activation of ERK1/2, whereas p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) had no effect on this process. In conclusion, these results indicate that Ang II can increase the expression of MMP-2 via AT1 receptor and ERK1/2 signaling pathways in human ASMCs and suggest that antagonists of AT1R and ERK1/2 may be useful for treating TAAs.
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, Beijing100037, 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, Beijing100037, 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, Beijing100037, China.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Sun
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, Beijing100037, China fwchangqian@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C544065:AGTR1 protein, human; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Angiotensin II; extracellular signal-regulated kinase 1/2; human aortic smooth muscle cells; matrix metalloproteinase-2; renin angiotensin system