{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T06:47:57Z","timestamp":1789195677585,"version":"build-2803163510"},"reference-count":44,"publisher":"American Physiological Society","issue":"4","funder":[{"name":"NIH","award":["R01 HL089405"],"award-info":[{"award-number":["R01 HL089405"]}]},{"name":"NIH","award":["R01 HL115265"],"award-info":[{"award-number":["R01 HL115265"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2016,2,15]]},"abstract":"<jats:p> 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<jats:sup>\u2212\/\u2212<\/jats:sup>, Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>, and Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>;MKK3<jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sup>\u2212\/\u2212<\/jats:sup>, Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>, and Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>;MKK3<jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sup>\u2212\/\u2212<\/jats:sup>;MKK3<jats:sup>\u2212\/\u2212<\/jats:sup> 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<jats:sup>\u2212\/\u2212<\/jats:sup>, Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>, and Akt-1<jats:sup>\u2212\/\u2212<\/jats:sup>;MKK3<jats:sup>\u2212\/\u2212<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajpcell.00194.2015","type":"journal-article","created":{"date-parts":[[2016,1,7]],"date-time":"2016-01-07T03:49:04Z","timestamp":1452138544000},"page":"C270-C283","source":"Crossref","is-referenced-by-count":41,"title":["Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts"],"prefix":"10.1152","volume":"310","author":[{"given":"Jianfeng","family":"Du","sequence":"first","affiliation":[{"name":"Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, 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