Abstract 15431: Pressure Overload Causes PTP1B Activation – a Possible Mechanism for Heart Failure Associated Insulin Resistance
Cardiac insulin resistance has been suggested as possible cause for contractile dysfunction. We investigated cardiac insulin sensitivity (cIR) in rats developing pressure overload (PO) heart failure and in left ventricles from patients with or without aortic stenosis and preserved or impaired ejection fraction (EF).
Methods and Results: Male Sprague-Dawley rats were subjected to PO by transverse aortic constriction for 2, 10 and 20 weeks. PO caused hypertrophy (LVPWD 1,69±0,56 vs. 2,35±0,51mm, p<0,05) with normal systolic function up to 10 weeks (EF 74,7±1,7 vs. 67,5±3,3%; FS 45,6±1,6 vs. 39,7±2,7%, ns) and impaired systolic function at 20 weeks (EF: 68,2±2,0 vs. 47,8±1,6 %; p<0,05; FS: 45,6± vs. 29,4±1,0%; p<0,05). In isolated working hearts, insulin response was normal at 2 weeks of PO (ΔGO 2w: 0,98±0,26 vs. 0,69±0,13 μmol/min/gdry, ns) and significantly reduced after 10 and 20 weeks (ΔGO 10w: 0,88±0,16 vs. 0,29±0,05, 20w: 0,95±0,16 vs.±0,04 μmol/min/gdry; p<0,05), indicating the onset of cIR before impairment of systolic function. Euglycemic-hyperinsulinemic clamp studies confirmed the presence of cIR in heart failure in vivo (cardiac glucose uptake 57,7±4,8 vs. 35,4±6,3 mg/Kg/min, p<0.05). Systemic insulin sensitivity remained normal (glucose infusion rate 28,6±0,9 vs. 29,4±1,1 mg/Kg/min, n.s.). Concomitantly, the activity of the insulin-receptor tyrosine phosphatase PTP1B was elevated only after 10 and 20 weeks of PO (10w: 36,5±1,3 vs. 46,9±1,3; 20w: 34,4±0,9 vs. 48,0±1,6 U/g protein, both p<0,05), suggesting PTP activation as potential mechanism for cIR. Consistently, insulin-stimulated phosphorylation of the insulin receptor was reduced after 10 and 20 weeks of PO and so was insulin-induced Akt phosphorylation. Consistent with the findings in rats, increased PTP1B activity was also present in left ventricular myocardium from patients with aortic stenosis and impaired EF.
Conclusions: PTP1B is activated by pressure overload in both rats and humans. This activation explains reduced insulin signaling and can thereby cause cIR, a mechanism which seems to be relevant in patients.
- © 2010 by American Heart Association, Inc.