Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone + salt-induced cardiac fibrosis in vivo

Srinivas Mummidi, Nitin A Das, Andrea J Carpenter, Hemanthkumar Kandikattu, Maike Krenz, Ulrich Siebenlist, Anthony J. Valente, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The overall goals of this study were to investigate whether metformin exerts anti-fibrotic effects in aldosterone (Aldo) + salt-treated wild type mouse hearts, and determine the underlying molecular mechanisms in isolated adult cardiac fibroblasts (CF). In vitro, Aldo induced CF activation, migration, and proliferation, and these effects were inhibited by metformin. Further, Aldo induced PPM1A (Protein Phosphatase Magnesium Dependent 1A) activation and inhibited AMPK phosphorylation. At a pharmacologically relevant concentration, metformin restored AMPK activation, and inhibited Aldo-induced Nox4/H2O2-dependent TRAF3IP2 induction, pro-inflammatory cytokine expression, and CF migration and proliferation. Further, metformin potentiated the inhibitory effects of spironolactone, a mineralocorticoid receptor antagonist, on Aldo-induced collagen expression, and CF migration and proliferation. These results were recapitulated in vivo, where metformin reversed Aldo + salt-induced oxidative stress, suppression of AMPK activation, TRAF3IP2 induction, pro-inflammatory cytokine expression, and cardiac fibrosis, without significantly modulating systolic blood pressure. These in vitro and in vivo data indicate that metformin has the potential to reduce adverse cardiac remodeling in hypertensive heart disease.

Original languageEnglish (US)
Pages (from-to)95-102
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume98
DOIs
StatePublished - Sep 1 2016

Keywords

  • Aldosterone
  • AMPK activators
  • Cardiac fibrosis
  • Metformin
  • TRAF3IP2

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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