Title |
Metabolically-inactive glucagon-like peptide-1(9–36)amide confers selective protective actions against post-myocardial infarction remodelling
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Published in |
Cardiovascular Diabetology, April 2016
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DOI | 10.1186/s12933-016-0386-5 |
Pubmed ID | |
Authors |
Emma Robinson, Mitchel Tate, Samuel Lockhart, Claire McPeake, Karla M. O’Neill, Kevin S. Edgar, Danielle Calderwood, Brian D. Green, Barbara J. McDermott, David J. Grieve |
Abstract |
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. 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. Adult 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. Infarct 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. These 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 2% |
Unknown | 50 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 9 | 18% |
Student > Master | 7 | 14% |
Student > Ph. D. Student | 6 | 12% |
Student > Bachelor | 4 | 8% |
Student > Doctoral Student | 3 | 6% |
Other | 8 | 16% |
Unknown | 14 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 20 | 39% |
Biochemistry, Genetics and Molecular Biology | 4 | 8% |
Agricultural and Biological Sciences | 4 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 4% |
Economics, Econometrics and Finance | 1 | 2% |
Other | 3 | 6% |
Unknown | 17 | 33% |