Metabolically-inactive glucagon-like peptide-19–36amide confers selective protective actions against post-myocardial infarction remodellingReportar como inadecuado




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Cardiovascular Diabetology

, 15:65

First Online: 14 April 2016Received: 13 February 2016Accepted: 07 April 2016 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-19–36amide, also appears to exert notable cardiovascular effects, including protection against acute cardiac ischaemia. Here, we specifically studied the influence of GLP-19–36amide 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-19–36amide or vehicle control for 4 weeks.

ResultsInfarct size was similar between groups with no effect of GLP-19–36amide 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-19–36amide 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-19–36amide. Cardiac macrophage infiltration was also reduced by GLP-19–36amide 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-19–36amide versus exendin-4.

ConclusionsThese data suggest that GLP-19–36amide 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.

KeywordsGlucagon-like peptide-1 GLP-1 GLP-19–36amide Myocardial infarction Cardiac remodelling AbbreviationsDPP-4dipeptidyl peptidase-4

IVSDinterventricular septal thickness in diastole

ECMextracellular matrix

GLP-1glucagon-like-peptide-1

GLP-1Rglucagon-like-peptide-1 receptor

LVleft ventricle

LVEDDleft ventricular end-diastolic diameter

LVEDVleft ventricular end-diastolic volume

LVESDleft ventricular end-systolic diameter

LVESVleft ventricular end-systolic volume

MImyocardial infarction

RT-PCRreverse transcription polymerase chain reaction

ROSreactive oxygen species

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Autor: Emma Robinson - Mitchel Tate - Samuel Lockhart - Claire McPeake - Karla M. O’Neill - Kevin S. Edgar - Danielle Calderwo

Fuente: https://link.springer.com/article/10.1186/s12933-016-0386-5







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