Metabolically-inactive glucagon-like peptide-1(9–36)amide confers selective protective actions against post-myocardial infarction remodelling

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.

Why is it so difficult to measure glucagon-like peptide-1 in a mouse?

“…It has been suggested that GLP-1(9-36)NH 2 may have effects on glucose homeostasis [43] and on the cardiovascular system [44][45][46]. In rodents, fragments of the GLP-1 metabolite may also have glucoregulatory effects, possibly mediated through hepatocytes [39], in line with previous observations of degradation of the GLP-1 metabolite [10,40].…”

The Cardiovascular Biology of Glucagon-like Peptide-1

“…Similarly, continuous infusion of GLP-1(9-36), 25 nmol/kg/day for 4 weeks, in female C57BL/6 mice following permanent left anterior descending coronary artery ligation did not modify body weight, plasma glucose, or infarct size. However, the extent of diastolic dysfunction was significantly attenuated, and pro-inflammatory cytokine expression and macrophage infiltration were reduced in hearts of GLP-1(9-36)amide-treated mice (Robinson et al, 2016). Although mechanisms linking GLP-1(9-36) or GLP-1(28-36) to improved ventricular function remain poorly defined, direct cardioprotective actions of GLP-1(9-36) remain evident in hearts or CMs from Glp1r À/À mice (Ban et al, 2008(Ban et al, , 2010.…”

Glucagon‐like peptide‐1 cleavage product GLP‐1 (9‐36) amide enhances hippocampal long‐term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation

“…GLP‐1R mediates most, if not all of the biological effects of GLP‐1 (7–36) amide (Campbell & Drucker, ; During et al, ). In contrast, whether GLP‐1 (9–36) functions through GLP‐1R remains unclear (Ban et al, ; Nikolaidis et al, ; Poudyal, ; Robinson et al, ). To further elucidate mechanisms associated with the LTP‐enhancing effects by GLP‐1 (9–36), we co‐administered (via i.p.…”

“…3.6 | The enhancement of hippocampal LTP induced by GLP-1 (9-36) treatment in vivo is blunted with administration of GLP-1 receptor antagonist exendin (9-39)amide GLP-1R mediates most, if not all of the biological effects of GLP-1 (7-36) amide (Campbell & Drucker, 2013;During et al, 2003). In contrast, whether GLP-1 (9-36) functions through GLP-1R remains unclear (Ban et al, 2008;Nikolaidis et al, 2005;Poudyal, 2016;Robinson et al, 2016). To further elucidate mechanisms associated with the LTPenhancing effects by GLP-1 (9-36), we co-administered (via i.p.…”

“…For instance, multiple lines of evidence demonstrate that GLP‐1(9–36) exerts beneficial cardiovascular effects including protection from experimental animal models of cardiac infarction/ischemia and dilated cardiomyopathy. Whether these cardioprotective effects are dependent on GLP‐1R remains elusive (Ban et al, ; Nikolaidis, Elahi, Shen, & Shannon, ; Poudyal, ; Robinson et al, ). Further, GLP‐1(9–36) alleviates and normalizes production of reactive oxygen species (ROS) associated with a model of hyperglycemia in human aortic endothelia cells (Giacco et al, ).…”