TY - JOUR
T1 - Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone + salt-induced cardiac fibrosis in vivo
AU - Mummidi, Srinivas
AU - Das, Nitin A.
AU - Carpenter, Andrea J.
AU - Kandikattu, Hemanthkumar
AU - Krenz, Maike
AU - Siebenlist, Ulrich
AU - Valente, Anthony J.
AU - Chandrasekar, Bysani
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - AMPK activators
KW - Aldosterone
KW - Cardiac fibrosis
KW - Metformin
KW - TRAF3IP2
UR - http://www.scopus.com/inward/record.url?scp=84979609999&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84979609999&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2016.07.006
DO - 10.1016/j.yjmcc.2016.07.006
M3 - Article
C2 - 27423273
AN - SCOPUS:84979609999
SN - 0022-2828
VL - 98
SP - 95
EP - 102
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -