Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: Implication for the therapeutic effect of statin in atrial structural remodeling

Chia Ti Tsai, Ling Ping Lai, Kuan Ting Kuo, Juey Jen Hwang, Chia Shan Hsieh, Kuan Lih Hsu, Chuen Den Tseng, Yung Zu Tseng, Fu Tien Chiang, Jiunn Lee Lin

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

BACKGROUND - Recently, activation of the local renin-angiotensin system and mitogen-activated protein kinase pathways in atrial myocardium has been found to play an important role in atrial structural remodeling related to atrial fibrillation. Another important mediator of the angiotensin II (Ang II) effect is the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has never been characterized in the atrium. METHODS AND RESULTS - In cultured atrial myocytes and fibroblasts, Ang II induced tyrosine phosphorylation of STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant-negative Rac1, losartan, and simvastatin. In atrial myocytes, activation of STAT3 by Rac1 was mediated by direct association of Rac1 with STAT3; however, in atrial fibroblasts, it was mediated by an indirect paracrine effect. Constitutively active STAT3 increased protein synthesis, and dominant-negative STAT3 abrogated Ang II-induced protein synthesis in atrial myocytes and fibroblasts. Rats infused long term with Ang II exhibited higher levels of activated Rac1, phospho-STAT3, collagen synthesis, and atrial fibrosis in the atria, all of which were attenuated by oral losartan and simvastatin. In human atrial tissues from patients with atrial fibrillation, Ang II and phospho-STAT3 levels were also elevated. CONCLUSIONS - The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II-induced atrial structural remodeling in atrial fibrillation.

Original languageEnglish
Pages (from-to)344-355
Number of pages12
JournalCirculation
Volume117
Issue number3
DOIs
Publication statusPublished - Jan 1 2008
Externally publishedYes

Keywords

  • Angiotensin II
  • Atrial fibrillation
  • Rac1 protein
  • Signal transduction
  • Small GTPases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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