Abstract 15595: Protein Tyrosine Phosphatase 1B Knockout Attenuates Obesity-Induced Cardiomyopathy
Obesity, type 2 diabetes and other features of metabolic syndrome are major risk factors for cardiovascular diseases. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin action. However, the role of PTP1B in obesity-related cardiomyopathy is unknown. This study was designed to evaluate the effect of genetic disruption of PTP1B on cardiac function in diet-induced obesity. Cardiac function was evaluated in Wild-type (WT) and PTP1B-/- mice fed a low fat (10% calorie) or high fat diet (45% calorie) for 5 months. High fat diet intake resulted in larger body weight (41.5±4 vs. 28.2±1g), heart weight (HW) (146±6 vs. 123±6 mg) and glucose intolerance in WT mice, the effect of which was attenuated by PTP1B knockout (n=8-10, p<0.05). Echocardiography showed an increase in wall thickness, end diastolic diameter (2.92±0.16 vs. 2.69±0.08 mm), end systolic diameter (1.73±0.12 vs. 1.33 ±0.06 mm) and a decrease in fractional shortening (39.7±1.4 vs. 51.4 ±2.1) following HFD which were significantly reconciled by PTP1B knockout (n=8-10, p<0.05). In addition, assessment of cardiomyocyte contractile function revealed decreased peak shortening, maximal velocity of shortening and relengthening following HFD feeding, the effect of which was rescued by PTP1B knockout (n=110-120 cells from 3 mice, p<0.05). High fat diet feeding resulted in increased cardiomyocytes cross-sectional area (330±0.05 vs. 233±0.04µm2) and hypertrophic proteins ANP and GATA4, which were significantly attenuated in PTP1B knockout mice (n=3-4 mice, p<0.05). Furthermore, Western blot analysis revealed high fat feeding upregulated Akt and mTOR phosphorylation and decreased AMPK and ACC phosphorylation in WT mice. Interestingly, PTP1B knockout caused a significant increase in phosphorylation of AMPK and ACC without affecting Akt and mTOR phosphorylation. In vitro silencing of PTP1B using siRNA dampened the expression of hypertrophic genes while it promoted AMPK phosphorylation. In conclusion, our data revealed that PTP1B knockout prevented obesity-induced cardiomyopathy by preserving AMPK signaling, suggesting the therapeutic promise of this enzyme in the treatment of obesity-induced cardiac anomalies.
- © 2012 by American Heart Association, Inc.