Abstract
BackgroundGlucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. In addition to GLP-1 receptor activation, the metabolically-inactive breakdown product, GLP-1(9–36)amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-1(9–36)amide on chronic post-myocardial infarction (MI) remodelling, which is a major driver of heart failure progression.MethodsAdult female C57BL/6 J mice were subjected to permanent coronary artery ligation or sham surgery prior to continuous infusion with GLP-1(9–36)amide or vehicle control for 4 weeks.ResultsInfarct size was similar between groups with no effect of GLP-1(9–36)amide on MI-induced cardiac hypertrophy, although modest reduction of in vitro phenylephrine-induced H9c2 cardiomyoblast hypertrophy was observed. Whilst echocardiographic systolic dysfunction post-MI remained unchanged, diastolic dysfunction (decreased mitral valve E/A ratio, increased E wave deceleration rate) was improved by GLP-1(9–36)amide treatment. This was associated with modulation of genes related to extracellular matrix turnover (MMP-2, MMP-9, TIMP-2), although interstitial fibrosis and pro-fibrotic gene expression were unaltered by GLP-1(9–36)amide. Cardiac macrophage infiltration was also reduced by GLP-1(9–36)amide together with pro-inflammatory cytokine expression (IL-1β, IL-6, MCP-1), whilst in vitro studies using RAW264.7 macrophages revealed global potentiation of basal pro-inflammatory and tissue protective cytokines (e.g. IL-1β, TNF-α, IL-10, Fizz1) in the presence of GLP-1(9–36)amide versus exendin-4.ConclusionsThese data suggest that GLP-1(9–36)amide confers selective protection against post-MI remodelling via preferential preservation of diastolic function, most likely due to modulation of infiltrating macrophages, indicating that this often overlooked GLP-1 breakdown product may exert significant actions in this setting which should be considered in the context of GLP-1 therapy in patients with cardiovascular disease.
Highlights
Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus
With regard to cardiac ischaemia, protective actions of glucagon-like peptide-1 (GLP1)(7–36)amide and exendin-4 against reperfusion injury were found to be resistant to the GLP-1 receptor (GLP-1R) antagonist, exendin(9–39), and to persist in GLP-1R knockout mice, with the former being inhibited by the dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, indicating that they were likely to be mediated by GLP-1(9–36) and/or GLP-1R-independent pathways [5, 23]
Cardiomyocyte hypertrophy Chronic infusion with GLP-1(9–36) had no effect on MIinduced myocardial hypertrophy, as assessed by echocardiographic interventricular septal thickness in diastole (IVSD) (Fig. 1c) and cardiac morphometry, in vitro phenylephrine-induced hypertrophy of H9c2 cardiomyoblasts was reduced by GLP-1(9–36) (Fig. 1f)
Summary
Glucagon-like peptide-1 (GLP-1) therapies are routinely used for glycaemic control in diabetes and their emerging cardiovascular actions have been a major recent research focus. Robinson et al Cardiovasc Diabetol (2016) 15:65 regard to potential cardiovascular applications of GLP-1 therapy, one of the most studied areas has been in the setting of ischaemic heart disease, to which diabetic patients are predisposed [14] It has been known for several years that both GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase endogenous GLP-1, protect cardiomyocytes from acute ischaemic damage and promote functional recovery after experimental myocardial infarction (MI) [15]. Acute treatment of ex vivo mouse hearts with GLP-1(9–36) prior to ischaemia–reperfusion resulted in improved functional recovery and reduced infarct size, and conferred additional cardioprotective actions to those mediated by exendin-4 [24], suggesting that the metabolically-inactive GLP-1 peptide may activate distinct cardiovascular signalling pathways. We report selective GLP-1(9–36)-mediated protection against diastolic dysfunction and myocardial inflammation post-MI together with specific modulation of macrophage response genes, actions which are clearly important to consider when assessing the likely effectiveness of GLP-1 targeting strategies in this setting
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