Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix.
Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.
Centre for Experimental Medicine, Institute of Clinical Science Block A, Queen's University Belfast, Grosvenor Road, Belfast, BT12 6BA, UK.
Emma
E
Robinson
Roslyn S
RS
Cassidy
Mitchel
M
Tate
Youyou
Y
Zhao
Samuel
S
Lockhart
Danielle
D
Calderwood
Rachel
R
Church
Mary K
MK
McGahon
Derek P
DP
Brazil
Barbara J
BJ
McDermott
Brian D
BD
Green
David J
DJ
Grieve
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D000077270:Exenatide; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D010455:Peptides; D014688:Venoms; D000077270:Exenatide