Adiponectin protects against angiotensin II-induced cardiac fibrosis through activation of PPAR-alpha.
OBJECTIVE
Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II).


RESULTS
Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-alpha knockout (PPAR-alpha-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II-infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-alpha-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal-regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-alpha activity, whereas the adiponectin-dependent PPAR-alpha activation was diminished by Compound C, an inhibitor of AMPK.


CONCLUSIONS
The present study suggests that adiponectin protects against Ang II-induced cardiac fibrosis possibly through AMPK-dependent PPAR-alpha activation.
Fujita
Koichi
K
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5, Yamada-oka, Suita, Osaka 565-0871, Japan.
Maeda
Norikazu
N
Sonoda
Mina
M
Ohashi
Koji
K
Hibuse
Toshiyuki
T
Nishizawa
Hitoshi
H
Nishida
Makoto
M
Hiuge
Aki
A
Kurata
Akifumi
A
Kihara
Shinji
S
Shimomura
Iichiro
I
Funahashi
Tohru
T
D000091162:AMP-Activated Protein Kinase Kinases; D000256:Adenoviridae / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology
D052242:Adiponectin; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D011494:Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases