Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 310, Issue 4, Pages C270-C283Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00194.2015
Keywords
glucagon-like peptide-1 receptor; MAPK kinase 3; Akt-1; myocardial infarction; function
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Funding
- National Heart, Lung, and Blood Institute Grant [R01 HL089405, R01 HL115265]
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We have demonstrated that glucagon like peptide-1 (GLP-1) protects the heart against ischemic injury. However, the physiological mechanism by which GLP-1 receptor (GLP-1R) initiates cardioprotection remains to be determined. The objective of this study is to elucidate the functional roles of MAPK kinase 3 (MKK3) and Akt-1 in mediating exendin-4-elicited protection in the infarcted hearts. Adult mouse myocardial infarction (MI) was created by ligation of the left descending artery. Wild-type, MKK3(-/-), Akt-1(-/-), and Akt-1(-/-); MKK3(-/-) mice were divided into one of several groups: 1) sham: animals underwent thoracotomy without ligation; 2) MI: animals underwent MI and received a daily dose of intraperitoneal injection of vehicle (saline); 3) MI + exendin-4: infarcted mice received daily injections of exendin-4, a GLP-1R agonist (0.1 mg/kg, ip). Echocardiographic measurements indicate that exendin-4 treatment resulted in the preservation of ventricular function and increases in the survival rate, but these effects were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-); MKK3(-/-) mice. Exendin-4 treatments suppressed cardiac hypotrophy and reduced scar size and cardiac interstitial fibrosis, respectively, but these beneficial effects were lost in genetic elimination of MKK3, Akt-1, or Akt-1(-/-); MKK3(-/-) mice. GLP-1R stimulation stimulated angiogenic responses, which were also mitigated by deletion of MKK3 and Akt-1. Exendin-4 treatment increased phosphorylation of MKK3, p38, and Akt-1 at Ser129 but decreased levels of active caspase-3 and cleaved poly (ADP-ribose) polymerase; these proteins were diminished in MKK3(-/-), Akt-1(-/-), and Akt-1(-/-); MKK3(-/-) mice. These results reveal that exendin-4 treatment improves cardiac function, attenuates cardiac remodeling, and promotes angiogenesis in the infarcted myocardium through MKK3 and Akt-1 pathway.
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