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49 Glucagon-like peptide-1 protects against cardiac remodelling after myocardial infarction via specific actions on the extracellular matrix
  1. E Robinson1,
  2. R S Cassidy1,
  3. B J McDermott1,
  4. B D Green2,
  5. D J Grieve1
  1. 1Queen's University Belfast, Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Grosvenor Road, Belfast, UK
  2. 2Queen's University Belfast, Human Nutrition and Health Group, School of Biological Sciences, Stranmillis Road, Belfast, UK

Abstract

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically-approved for glycaemic control in type 2 diabetes, which also has important cardiovascular actions. Several groups have shown that GLP-1 protects cardiomyocytes from acute ischaemic damage. Here, we investigated whether exendin-4, a stable GLP-1 mimetic, has beneficial effects on chronic cardiac remodelling following myocardial infarction (MI). Adult normoglycaemic C57BL/6J female mice (8–10 weeks) were subjected to coronary artery ligation or sham surgery and chronically-infused with exendin-4 (25 nmol/kg/day) or vehicle for 4 weeks (n‰¥18). Echocardiography indicated that exendin-4 protected against left ventricular (LV) systolic (ejection fraction: sham, 57.8±8.6 vs MI, 43.5%±6.5%, p<0.05; sham exendin-4, 55.0±7.9 vs MI exendin-4, 48.3%±9.7%) and diastolic dysfunction (E/A ratio: sham, 1.98±0.58 vs MI, 1.52±0.58, p<0.05; sham exendin-4, 1.86±0.44 vs MI exendin-4, 1.71±0.73) and attenuated LV chamber dilatation (end-diastolic diameter: sham, 6.8±2.3 vs MI, 12.8±5.8 mm, p<0.05; sham exendin-4, 7.1±2.0 vs MI exendin-4, 10.5±4.1 mm). Interestingly, exendin-4 had no effect on cardiac hypertrophy, as assessed by morphometry/histology but exerted specific actions on the extracellular matrix as indicated by attenuation of MI-induced increases in interstitial fibrosis (MI, 9.65±2.83 vs MI exendin-4, 4.73%±1.10%, p<0.05) and pro-fibrotic/inflammatory gene expression (TGF-β: sham, 1.05±0.35 vs MI, 1.59±0.56, p<0.05; sham exendin-4, 0.95±0.25 vs MI exendin-4, 1.11±0.36), together with elevated decreases in MMP-9 expression post-MI (control, 19±73 vs exendin-4, 158%±122%, p<0.05). These results indicate that GLP-1 protects the ischaemic heart against contractile dysfunction post-MI via differential actions on key components of the remodelling phenotype, which may support its use as a novel therapeutic strategy in this setting.

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