Evidence for the Importance of Adiponectin in the Cardioprotective Effects of Pioglitazone

Abstract

Abstract-The favorable effects of the peroxisome proliferator-activated receptor-␥ 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-␤1 in the heart. Treatment of wild-type mice with pioglitazone attenuated cardiac hypertrophy and fibrosis, extracellular signal-regulated kinase phosphorylation, and transforming growth factor-␤1 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. (Hypertension. 2010;55:69-75.)

Comparative Study of the Protective Effect of Metformin and Sitagliptin against Doxorubicin-Induced Cardiotoxicity in Rats

“…Adiponectin is an adipokine synthesized in the adipose tissue, exerts vasodilator, anti-apoptotic, anti-inflammatory and anti-oxidative activities in both cardiac and vascular cells [44] and attenuate the apoptosis induced by doxorubicin [45].…”

AMP-Activated Protein Kinase Mediates the Antiplatelet Effects of the Thiazolidinediones Rosiglitazone and Pioglitazone

“…An indirect effect on AMPK cannot be excluded either. Thiazolidinediones, for example, may activate platelet AMPK indirectly by increasing expression and secretion of adiponectin, which is positively regulated by PPARg and activates AMPK in various tissues (Higuchi et al, 2010;Li et al, 2010). Because of these redundancies, it is complicated to demonstrate our present findings in animal experiments.…”

Pioglitazone prevents intimal hyperplasia in experimental rabbit vein grafts

“…Treatment with pioglitazone was initiated 1 week before surgery and continued for 4 weeks as a food admixture (3 mg/kg/d), consistent with previous reports. 13,14 Vein graft implantation. Rabbits underwent reversed autologous vein bypass grafting of the right common carotid artery using the external jugular vein, as described previously.…”