Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0476-7) contains supplementary material, which is available to authorized users.

Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages

“…Our results showed that GLP-1 treatment reduced the release of the inflammatory cytokines TNF-α, IL-6, and IL-1β in LPS-stimulated macrophages. These results are consistent with previous observations that GLP-1 inhibits the secretion of IL-1β and TNF-α in vitro (18) as well as IL-1β and IL-6 in vivo (35). Our observations taken together with previous studies suggest that GLP-1 has anti-inflammatory properties in macrophages.…”

Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis

“…33,34 We found that the decline in the casual GLP-1 level contributes to the increased cardiac apoptosis in TAC/CON by demonstrating not only the effects of DPP4i but also those GLP-1 antagonist in vivo (Figures 3 and 4). One of the possible explanations for the pathological decline in the GLP-1 level can be found in the previous evidences demonstrating that circulating DPP4 activity is augmented in nondiabetic HF 4,5,35 because the DPP4 protease specifically truncates GLP-1.…”

IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation

“…In young mice, IL-10 deficiency has less impressive effects, despite significantly elevating myocardial TNF-α and CCL2 [61]. Exendin-4 elevated IL-10 expression, which was associated with a cardioprotective effect on post-MI cardiac remodeling [46]. Kishore et al showed that subcutaneous injection of IL-10 post-MI reduced LV dysfunction and infarct wall thinning [25].…”