Glucagon-Like Peptide-1 Analog Liraglutide Attenuates Pressure-Overload Induced Cardiac Hypertrophy and Apoptosis through Activating ATP Sensitive Potassium Channels

Purpose This study aimed to investigate whether inhibition of glucagon-like peptide-1 (GLP-1) on pressure overload induced cardiac hypertrophy and apoptosis is related to activation of ATP sensitive potassium (KATP) channels. Methods Male SD rats were randomly divided into five groups: sham, control (abdominal aortic constriction), GLP-1 analog liraglutide (0.3 mg/kg/twice day), KATP channel blocker glibenclamide (5 mg/kg/day), and liraglutide plus glibenclamide. Results Relative to the control on week 16, liraglutide upregulated protein and mRNA levels of KATP channel subunits Kir6.2/SUR2 and their expression in the myocardium, vascular smooth muscle, aortic endothelium, and cardiac microvasculature. Consistent with a reduction in aortic wall thickness (61.4 +/- 7.6 vs. 75.0 +/- 7.6 mu m,p < 0.05), liraglutide enhanced maximal aortic endothelium-dependent relaxation in response to acetylcholine (71.9 +/- 8.7 vs. 38.6 +/- 4.8%,p < 0.05). Along with a reduction in heart to body weight ratio (2.6 +/- 0.1 vs. 3.4 +/- 0.4, mg/g,p < 0.05) by liraglutide, hypertrophied cardiomyocytes (371.0 +/- 34.4 vs. 933.6 +/- 156.6 mu m(2),p < 0.05) and apoptotic cells (17.5 +/- 8.2 vs. 44.7 +/- 7.9%,p < 0.05) were reduced. Expression of anti-apoptotic protein BCL-2 and contents of myocardial ATP were augmented, and expression of cleaved-caspase 3 and levels of serum Tn-I/-T were reduced. Echocardiography and hemodynamic measurement showed that cardiac systolic function was enhanced as evidenced by increased ejection fraction (88.4 +/- 4.8 vs. 73.8 +/- 5.1%,p < 0.05) and left ventricular systolic pressure (105.2 +/- 10.8 vs. 82.7 +/- 7.9 mmHg,p < 0.05), and diastolic function was preserved as shown by a reduction of ventricular end-diastolic pressure (-3.1 +/- 2.9 vs. 6.7 +/- 2.8 mmHg,p < 0.05). Furthermore, left ventricular internal diameter at end-diastole (5.8 +/- 0.5 vs. 7.7 +/- 0.6 mm,p < 0.05) and left ventricular internal diameter at end-systole (3.0 +/- 0.6 vs. 4.7 +/- 0.4 mm,p < 0.05) were improved. Dietary administration of glibenclamide alone did not alter all the parameters measured but significantly blocked liraglutide-exerted cardioprotection. Conclusion Liraglutide ameliorates cardiac hypertrophy and apoptosis, potentially via activating KATP channel-mediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.