title: Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo.
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.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mummidi
authors.affiliation: Department of Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Nitin A
authors.initials: NA
authors.lastname: Das
authors.affiliation: Department of Cardiothoracic Surgery, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Carpenter
authors.affiliation: Medicine/Cardiology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Hemanthkumar
authors.initials: H
authors.lastname: Kandikattu
authors.affiliation: Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Krenz
authors.affiliation: Laboratory of Immunoregulation, NIAID/NIH, Bethesda, MD 20892, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.affiliation: Medicine/Cardiology, University of Missouri School of Medicine, Columbia, MO 65211, USA; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65201, USA. Electronic address: chandrasekarb@health.missouri.edu.
authors.forename: Bysani
authors.initials: B
authors.lastname: Chandrasekar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006861:Hydrogen Peroxide / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism*; D000071636:Protein Phosphatase 2C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; C515963:Traf3ip2 protein, mouse; D000450:Aldosterone; D003094:Collagen; D008687:Metformin; D006861:Hydrogen Peroxide; D055372:AMP-Activated Protein Kinases; C000607466:Ppm1a protein, mouse; D000071636:Protein Phosphatase 2C
keywords: AMPK activators; Aldosterone; Cardiac fibrosis; Metformin; TRAF3IP2