Abstract 12646: Cardioprotective Effects of Dipeptidyl Peptidase-4 Inhibition on Pressure Overload-induced Heart Failure in Mice
Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors are newly available drugs for diabetes mellitus, but its effects on pressure overload-induced heart failure are not known.
Methods: The expression level of DPP-4 on cardiomyocytes under hypoxic condition for 24 hours was determined by immunostaining and western blot. 8-week-old C57BL/6 mice were treated with high fat diet (HFD) plus DPP-4 inhibitor (MK-626, 3mg/kg/day) (MK, n=17) or HFD alone (control, n=16) after transverse aortic constriction (TAC). We also performed TAC on DPP-4 knockout mice (DPP-4-/-) (n=10). Left ventricular function was assessed by echocardiography at 2 weeks after TAC. The number of vessels in myocardium, the cell surface area of cardiomyocyte and myocardial fibrosis were assessed at 2 weeks.
Results: We first confirmed that DPP-4 protein was expressed on rat neonatal cardiomyocytes under hypoxic condition. As DPP-4 is known to inactivate SDF-1 which has direct protective effects on cardiomyocytes, we next evaluated the effects of DPP-4 inhibition on pressure overload-induced heart failure in mice. In TAC mice model, DPP-4 inhibitor significantly improved fractional shortening (FS), but it did not change left ventricular diameter (LVDd) and intraventricular wall thickness at end-diastole (IVSTd) (FS (%); sham, 44.0±1.6, control, 40.9±1.5, MK, 46.4±1.4, p<0.05, LVDd (mm); sham, 36.9±1.0, control, 32.0±0.8, MK, 31.6±0.6, p=NS, IVSTd (mm); sham,0.8±0.1, control,1.2±0.0, MK,1.2±0.0, p=NS). DPP-4 inhibitor decreased the degree of left ventricular fibrosis (sham, 1.9±0.2%, control, 4.0±0.4%, MK, 2.9±0.3%, p<0.05) and increased the vessel number (control, 1.2±0.0, MK, 1.6±0.1 -fold relative to sham, p<0.05). The degree of cardiac hypertrophy was not different between control group and MK group (cell surface area of cardiomyocyte; control, 1.4±0.1, MK,1.4±0.1 -fold relative to sham). Blood glucose levels were not associated with the cardioprotective effects of DPP-4 inhibitor. These cardioprotective effects were recognized in DPP-4-/- mice after TAC.
Conclusion: DPP-4 inhibition may ameliorate the progression of heart failure through the inhibition of fibrosis and the increase in vessel number in pressure overload-induced heart.
- © 2012 by American Heart Association, Inc.