Abstract 20406: Stimulation of Glucagon-Like-Peptide-1 Receptor Elicits the Protection Through Akt-1 in Infarcted Hearts
Background: We have demonstrated that GLP-1 protects the heart against ischemia and reperfusion injury. However, it remains unknown whether the stimulation of GLP-1 receptor (GLP-1R) that initiates cardioprotection is mediated by Akt-1 pathway.
Objectives: The goal of this study is to elucidate the functional roles of Akt-1 in mediating GLP-1 receptor-elicited protection in infarcted hearts.
Methods: Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Both wild type (C57BL/6) and Akt-1-/- mice were divided into one of three groups as following: 1) Sham: Animals underwent thoracotomy without ligation; 2) MI: Animals underwent MI and received a daily dose of intraperitoneal injection (i.p.) of vehicle (saline); 3) MI + Exendin-4: MI mice received daily injections of exendin-4, a GLP-1 receptor agonist (0.1mg/kg, i.p.). Echocardiography was employed to measure ventricular function prior to and after myocardial infarction. Histological analysis was conducted to assess cardiac hypertrophy and interstitial fibrosis. Western blot was used to examine the levels of Akt-1 and apoptotic signaling pathway.
Results: Echocardiography showed a reduction in left ventricular ejection fraction (EF) and fraction shortening (FS) (41.8% ± 3.5; 17.1% ± 2.1) in WT after MI as compared to sham (81.7% ± 2.2; 44% ± 3.6, p<0.05, respectively). Exendin-4 improved both EF and FS (67.7% ±2.4; 32.3% ±1.5, p<0.05 vs MI), respectively. The improvement induced by Exendin-4 in EF and FS in MI mice was diminished in Akt-1-/- mice (35.5% ±4.4; 15.1% ± 3.3, p<0.05). Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis in the MI hearts, but these beneficial effects were absent in infarcted mice by elimination of Akt-1. GLP-1R stimulated angiogenesis in infarcted hearts, which were also mitigated by deletion of Akt-1. Furthermore, GLP-1R stimulation increased phosphorylation of Akt-1, decreased active-caspase 3, PARP and annexin V. Anti-apoptotic effects of Exendin-4 were diminished in Akt-1-/- mice.
Conclusion: GLP-1R stimulation improves cardiac function, attenuates remodeling, and promotes angiogenesis in the infarcted myocardium through the Akt-1 pathway.
Author Disclosures: J. Du: None. Y. Zhao: None. Y. Chen: None. T.C. Zhao: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.