title: Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts.
abstract: 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.
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Emergency Medicine, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Women and Infants Hospital, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
authors.forename: Yu Tina
authors.initials: YT
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Medicine, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Patrycja
authors.initials: P
authors.lastname: Dubielecka-Szczerba
authors.affiliation: Department of Plastic Surgery, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Department of Medicine, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Gangjian
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island; tzhao@bu.edu.
authors.forename: Ting C
authors.initials: TC
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000077270:Exenatide; D005355:Fibrosis; D048371:MAP Kinase Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D002316:Cardiotonic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse
keywords: Akt-1; MAPK kinase 3; function; glucagon-like peptide-1 receptor; myocardial infarction