title: Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together.
abstract: Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Yang
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
authors.forename: Sue
authors.initials: S
authors.lastname: Theus
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
authors.forename: Sharda
authors.initials: S
authors.lastname: Singh
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.
authors.forename: Madhu
authors.initials: M
authors.lastname: Budhiraja
authors.affiliation: Central Arkansas Veterans Healthcare System, and the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A. MehtaJL@UAMS.edu.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D054795:Incretins / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D000069476:Linagliptin / Q000494:pharmacology*; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002316:Cardiotonic Agents; D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D054795:Incretins; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D000069476:Linagliptin; D000069450:Liraglutide; D003094:Collagen; D019255:NADPH Oxidases
keywords: DPP-4 inhibitor; GLP-1 activator; ROS production; collagen expression; inflammation; myocardial ischaemia–reperfusion