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TRP X23 - Glucagon-like peptide-1 (GLP-1) modulates vascular inflammation in arterial hypertension – a cell-specific transcriptome analysis to identify new mechanistic pathways

Funding period: 01.02.2019 - 31.08.2020

Projekt Summary

Arterial hypertension is one of the leading risk factors for artherosclerosis and cardiovascular disease. Cardiovascular diseases culminate in thrombo-embolic events such as myocardial infarction or stroke. Arterial hypertension and endothelial function interact in a close relationship under the supreme reign of inflammatory processes and oxidative stress. The findings of basic research studies and clinical trials have accumulated substantial evidence for the concept that arterial hypertension is a genuine inflammatory disease. For instance, depletion of mononuclear phagocytes cells in angiotensin-II infused mice prevents a blood pressure increase and endothelial dysfunction. Furthermore, the clinical trial “CANTOS” uncovered that anti-inflammatory treatment of cardiovascular disease with a monoclonal antibody, targeting interleukin-1β, can improve the clinical outcome. However, the pathophysiologic mechanisms for the development of arterial hypertension are not completely understood. Genome-wide gene expression profiling offers novel possibilities for understanding the molecular processes culminating in arterial hypertension and cardiovascular diseases. Most important, new networks and pathways may be uncovered that could serve as potential targets for novel treatment strategies.

Glucagon like-peptide-1 (GLP-1) is a peptide hormone with known anti-inflammatory properties. It increases insulin release from beta-cells in the pancreas and its synthetic analogs are used for treatment of type 2 diabetes. The LEADER trial demonstrated that GLP-1 analogs reduce the risk of cardiovascular events in T2DM patients, an effect beyond glycemic control. Other clinical trials have investigated the effects of GLP-1 on cardiovascular disease and demonstrated cardioprotective effects after myocardial infarction, reduction of blood pressure and an improvement of endothelial dysfunction. Interestingly, it has been shown that GLP-1 levels in patients with coronary artery disease are reduced. Experimental studies have provided first evidence for the modulating effects of GLP-1 on inflammatory cells. It has been recently published that the GLP-1 degrading enzyme, dipeptidylpeptidase-4 (DPP4), promotes vascular adipose tissue inflammation and insulin resistance in obesity. However, a detailed evaluation of the precise mechanisms underlying the cardiovascular protective effects of GLP-1 has been hampered by the fact that the GLP-1 receptor is expressed on several different cell types in the vasculature. To address this gap in knowledge, we propose to use tissue-specific knock-out mice for the GLP-1 receptor in an ATII-induced model of hypertension. In detail, endothelium-specific and myeloid-specific Cre-lox mouse strains for the GLP1 receptor deletion will be studied for functional endpoints and, more importantly, transcriptome-wide gene expression differences. GLP-1 regulated candidate genes of interest will be further studied by CRISPR-Cas9 gene editing approaches in human cell lines.

Principal Investigators

 Markus Bosmann, MD
Markus Bosmann, MD

Juniorgroup leader, Internist, Adjunct Assistant Professor of Molecular Medicine

Associate Professor of Medicine, Pathology & Laboratory Medicine, Boston University

06131 17-8277