title: Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium.
abstract: We have demonstrated that GLP-1 improved myocardial functional recovery in acute myocardial ischemic injury. However, whether stimulation of the GLP-1 receptor (GLP-1R) with exendin-4, a selective GLP-1R agonist, could initiate a protective effect in the heart remains to be determined. Mouse myocardial infarction (MI) was created by ligation of the left descending artery. After 48 h of MI, animals were divided into the following groups (n = 5-7/group): 1) sham (animals that underwent thoracotomy without ligation), 2) MI [animals that underwent MI and received a daily dose of intraperitoneal injection (ip) of saline]; and 3) MI + exendin-4 [infarcted mice that received injections of exendin-4 (0.1 mg/kg ip)]. Two weeks later, cardiac function was assessed by echocardiography and an isovolumetrically perfused heart. Compared with control MI hearts, stimulation of GLP-1R improved cardiac function, which was associated with attenuation of myocardial hypertrophy, the mitigation of interstitial fibrosis, and an increase in survival rate in post-MI hearts. Furthermore, H9c2 cardiomyoblasts were preconditioned with exendin-4 at a dose of 100 nmol/l and then subjected to hydrogen peroxide exposure at concentrations of 50 and 100 μmol/l. The exendin-4 treatment decreased lactate dehydrogenase leakage and increased cell survival. Notably, this event was also associated with the reduction of cleaved caspase-3 and caspase-9 and attenuation of reactive oxygen species production. Exendin-4 treatments improved mitochondrial respiration and suppressed the opening of mitochondrial permeability transition pore and protected mitochondria function. Our results indicate that GLP-1R serves as a novel approach to eliciting cardioprotection and mitigating oxidative stress-induced injury.
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
authors.forename: Megan
authors.initials: M
authors.lastname: DeNicola
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 Surgery, Roger Williams Medical Center, Boston University Medical School, Boston University, Providence, Rhode Island;
authors.forename: Zhengke
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Women and Infants' Hospital of Rhode Island, Providence, Rhode Island;
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.affiliation: Department of Emergency.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio; and.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
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 Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island;
authors.forename: Shougang
authors.initials: S
authors.lastname: Zhuang
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; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control; D053208:Kaplan-Meier Estimate; D008297:Male; D008813:Mice, Inbred ICR; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D014463:Ultrasonography; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide
keywords: exendin-4; glucagon-like peptide-1 receptor; heart; infarction; oxidant stress