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

Abstract

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 μm, 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 μm 2 , p < 0.05) and apoptotic cells (17.5 ± 8.2 vs. 44.7 ± 7.9%, p < 0.05) were reduced. Expression of antiapoptotic 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 enddiastolic 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 channelmediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…Moreover, GLP-1R activation counteracts the effects of β-adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential [165]. Apart from maintaining calcium channel homeostasis, GLP-1RAs also activate ATPsensitive potassium channels to attenuate cardiac apoptosis and hypertrophy induced by pressure overload [166].…”

Glucagon‐like peptide‐1 receptor agonist treatment of high carbohydrate intake‐induced metabolic syndrome provides pleiotropic effects on cardiac dysfunction through alleviations in electrical and intracellular Ca2+ abnormalities and mitochondrial dysfunction

“…Supporting these statements, there are some in vitro and in vivo studies performed with GLP-1R agonists, which are providing further novel information at cellular levels. 7,9,19,22 In that line, recent studies demonstrated that a GLP-1R agonist, liraglutide protects cardiomyocytes from metabolic disturbance and mitochondrial dysfunction. 6,23 This agonist also regulates Ca 2+ -homeostasis, the electrophysiological activities of cardiomyocytes modulating Ca 2+ -handling proteins, 2,7 reduces ventricular arrhythmic potential, 8 and activates ATP-sensitive K + -channels.…”

“…[3][4][5] Interestingly, these agonists have a wide range of pleiotropic effects on the cardiovascular system, independent of the above effects. [6][7][8] In that regard, it has been shown with experimental studies on GLP-1R benefits in cardiomyocytes, 2,[6][7][8][9] and clinical outcomes on cardiovascular system abnormalities with their varied efficacy. [10][11][12][13][14][15] Physiologically, GLP-1 in the heart can drive myocardial glucose uptake and thereby provide protection against pathological stimuli such as myocardial ischaemic-injury.…”

“…[10][11][12][13][14][15] Physiologically, GLP-1 in the heart can drive myocardial glucose uptake and thereby provide protection against pathological stimuli such as myocardial ischaemic-injury. 2,9,[16][17][18][19] Both experimental and clinical studies emphasise that there are marked impaired myocardial GLP-1R agonist responses in obese, MetS, and diabetic individuals. [16][17][18][19] In these studies, it has been also demonstrated the important effects of GLP-1R agonists on key signal transduction associated with cardiomyocyte injury, and activation of post-conditioning protective pathways in the heart.…”

Eplerenone inhibites atrial autonomic nerve remodeling via the ERK1/2 MAPK pathway in a rabbit model of atrial fibrillation

“…Proteins were extracted from rabbit atria tissue specimens or HL-1 cells. The protein content was determined by using the Bradford method according to our previous study [19] . The same amount of protein (40μg) was loaded per lane and separated by 8-12% sodium dodecy1 sulfate-polyacrylamide gel electrophoresis.…”