Angiotensin II signals mechanical stretch-induced cardiac matrix metalloproteinase expression via JAK-STAT pathway

Tzong Luen Wang, Yu Hui Yang, Hang Chang, Chi Ren Hung

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Background. - Mechanical stress induces many pathophysiological effects in cardiomyocytes. The objective of this study was to test the hypothesis that angiotensin II is a potential mediator of stretch-induced activation of matrix metalloproteinases (MMP).Methods. - Neonatal rat cardiomyocytes grown on a flexible membrane were cyclically stretched achieving up to 20% elongation at 60 cycles/min (using a vacuum). We explored the signaling pathways involved in cyclical stretch-induced expression of MMP-14 and MMP-2.Results. - Cyclical mechanical stretch significantly increased mRNA expression and protein synthesis for MMP-14 and MMP-2 from the 6 th to 24 th h. The increase in MMP-14 and -2 proteins after stretch was completely blocked after the pretreatment with losartan (an angiotensin II AT1 receptor antagonist, 200 nM) and AG-490 (a Janus kinase 2 tyrosine kinase inhibitor, 100 nM) but not with PD 98059 (an inhibitor of p42/p44 mitogen-activated protein kinase, 50 μM) or wortmannin (a phosphatidylinositol 3-kinase, 30 nM). By zymography, MMP-2 activity was increased by cyclical stretch that was significantly attenuated by losartan and AG-490. The mechanical strain also increased the immunohistochemical labeling of MMP-14 and -2 that was attenuated by adding losartan. Cyclical stretch increased the expression of STAT-1 that was abolished by pretreating with losartan or AG-490 (50 μM and 100 μM).Conclusion. - These findings indicate that cyclical stretch induces MMP-14 and -2 expression in neonatal rat cardiomyocytes and that the induction is mediated by the angiotensin II-JAK-STAT1 pathway.

Original languageEnglish
Pages (from-to)785-794
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number3
DOIs
Publication statusPublished - Sep 2004

Keywords

  • Angiotensin II
  • Cardiomyocytes
  • Janus kinase/STAT1
  • Matrix metalloproteinase
  • Mechanical stretch
  • Wistar rat

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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