Angiotensin II downregulates ACE2-mediated enhancement of MMP-2 activity in human cardiofibroblasts.
Angiotensin converting enzyme II (ACE2) is a component of the renin-angiotensin system (RAS) that negatively regulates angiotensin II (Ang II). Ang II, in turn, affects the expression of matrix metalloproteinases (MMPs) to induce heart remodeling. The specific mechanisms by which ACE2 regulates MMP-2, however, remain unclear. The aim of this study was to investigate the regulatory relationships between Ang II, ACE2, and MMP-2. ACE2 expression was upregulated and downregulated in human cardiofibroblasts (HCFs) by lentiviral infection. Effects on MMP-2 activity, shed ACE2 activity, extracellular signal-regulated kinase (ERK) signaling pathway, and ADAM metallopeptidase domain 17 (ADAM17) expression were assessed. ACE2 increased MMP-2 activity, and Ang II inhibited this effect through the Ang II type-1 receptor (AT1R) and ERK1/2 signaling pathway. Ang II also reduced the effect of ACE2 on ERK1/2 levels, the activity of shed ACE2, and adam17 expression in HCFs. Additionally, these Ang II-mediated reductions could be attenuated by AT1R antagonist valsartan. In conclusion, these data help to clarify how ACE2 and Ang II interact to regulate MMP-2 and control tissue remodeling in heart disease.
a Department of Biological Science and Technology, National Chiao Tung University, No.75 Po-Ai Street, Hsinchu, Taiwan.
Tang-Ching
TC
Kuan
Mu-Yuan
MY
Chen
Yan-Chiou
YC
Liao
Li
L
Ko
Yi-Han
YH
Hong
Chun-Yi
CY
Yen
Wen-Yeh
WY
Hsieh
Kun-Shan
KS
Cheng
Chien-Liang
CL
Wu
Chih-Sheng
CS
Lin
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000068756:Valsartan; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D020778:Matrix Metalloproteinase 2; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D014633:Valine