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

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Notions of Conflict and 'New' Citizens' Inclusion:Post-Cosmopolitan Contestations in Germany

This chapter argues that there is a gap between symbolic exclusion from the national community when it comes to the inclusion of new German citizens of Turkish or Kurdish background, and a broad claim to be a cosmopolitan society, at large. While focusing on narratives of minority key political activists in Berlin, and analysing individual stories on the background of contemporary populist xenophobic debates and hate crime of the 1990s, the chapter illustrates both, individual success and vulnerability due to institutionalised forms of anti- Muslim and anti-Turks segments in Germany.