Abstract 16864: Adiponectin Mediates Cardioprotection in Oxidative Stress-Induced Cardiomyocyte Remodeling via AMPK Signaling
Background: Reactive oxygen species (ROS) induces matrix metalloproteinases (MMPs) that leads to adverse cardiac remodeling. Adiponectin (APN), an adipokine, decreases cardiac hypertrophy; but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the involved mechanisms.
Methods: Wild type (WT) and APN-deficient (APNKO) mice were infused with angiotensin (Ang)-II (3.2mg/kg/d) for 14 days, which induces ROS, hypertension and left ventricular hypertrophy (LVH). Hearts were stained for fibrosis. MMP-2, MMP-9, TIMP-1, TIMP-2, p-AMPK, and p-ERK expression were assessed by immunoblotting. Isolated adult rat ventricular myocytes (ARVM) were pre-treated with recombinant APN (30μg/mL, 18hrs) followed by H2O2 stimulation at physiologic concentrations (1–200μM). ARVM hypertrophy was measured by (3H)-leucine incorporation and ANF gene expression by RT-PCR. p-AMPK and p-ERK expression were determined by immunoblotting.
Results: Ang-II significantly worsened hypertension, LVH and fibrosis in APNKO vs. WT hearts. Ang-II increased myocardial p-ERK and significantly decreased p-AMPK expression by 50±5% and 105±4%, respectively in APNKO vs. WT hearts. The matrix markers MMP-2 and MMP-9 were significantly increased 63±3% and 133±3%, respectively in Ang-II WT hearts vs. control. Ang-II further increased MMP-2 and MMP-9 expression 15% and 22% respectively in APNKO vs. WT hearts (p<0.05 for both). Neither Ang-II nor APN-deficiency affected TIMP expression. In ARVM, protein synthesis and ANF expression were significantly increased 36±13% and 28±9% by H2O2 1μM and 200μM, respectively. APN significantly decreased H2O2-induced protein synthesis by 27±8% and ANF expression by 22±8%. APN significantly increased p-AMPK by 59±15% and 81±22% in both non-stimulated and H2O2 ARVM, respectively. Likewise, H2O2 induced p-ERK, by 2.2±0.3 fold (p<0.01), which was abrogated with APN by 29±6% (p<0.05).
Conclusions: APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling. Its effects on ROS and ultimately on MMP expression defines the protective role of APN against ROS-induced cardiac remodeling.
- © 2010 by American Heart Association, Inc.