title: Evidence for the importance of adiponectin in the cardioprotective effects of pioglitazone.
abstract: The favorable effects of the peroxisome proliferator-activated receptor-gamma ligand pioglitazone on glucose metabolism are associated with an increase in the fat-derived hormone adiponectin in the bloodstream. A recent clinical trial, Prospective Pioglitazone Clinical Trial in Macrovascular Events, demonstrated that pioglitazone improved cardiovascular outcomes in patients with type 2 diabetes mellitus. However, the functional role of adiponectin in cardioprotection by pioglitazone has not been examined experimentally. Here we investigated the effect of pioglitazone on angiotensin II (Ang II)-induced cardiac hypertrophy and assessed the potential contribution of adiponectin to the action of pioglitazone on the heart. Wild-type or adiponectin-deficient mice were treated with pioglitazone as food admixture at a concentration of 0.01% for 1 week followed by 2 weeks of infusion with Ang II at 3.2 mg/kg per day. Ang II infusion in wild-type mice resulted in exacerbated myocyte hypertrophy and increased interstitial fibrosis, which were accompanied by elevated phosphorylation of extracellular signal-regulated kinase and expression of transforming growth factor-beta1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-beta1 expression in response to Ang II. Pioglitazone also increased the plasma adiponectin level and phosphorylation of cardiac AMP-activated protein kinase in wild-type mice in the presence of Ang II. The suppressive effects of pioglitazone on Ang II-induced cardiac hypertrophy and fibrosis were diminished in adiponectin-deficient mice. Furthermore, pioglitazone had no effects on the phosphorylation of extracellular signal-regulated kinase and AMP-activated protein kinase in the Ang II-infused heart of adiponectin-deficient mice. These data provide direct evidence that pioglitazone protects against Ang II-induced pathological cardiac remodeling via an adiponectin-dependent mechanism.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Unno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.forename: Mayuko
authors.initials: M
authors.lastname: Furukawa
authors.forename: Taiki
authors.initials: T
authors.lastname: Ohashi
authors.forename: Xianwu
authors.initials: X
authors.lastname: Cheng
authors.forename: Kohzo
authors.initials: K
authors.lastname: Nagata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D024042:Collagen Type I / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D002316:Cardiotonic Agents; D024042:Collagen Type I; D024043:Collagen Type II; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone