Comprehensive characterization of cardiovascular protection by the GLP-1 (Glucagon-like peptide-1) analog liraglutide in experimental arterial hypertension
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Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a relatively new class of drugs that are approved for the treatment of type 2 diabetes mellitus. Additional to their blood glucose-lowering effect, cardiovascular outcome trials (CVOTs) revealed that long-acting GLP-1RAs including liraglutide significantly reduce the risk for cardiovascular events in diabetic patients with established cardiovascular disease. Until today, the mechanism and cellular components underlying the cardiovascular benefit of liraglutide, as well as its dependence on glycemic control, have only been incompletely understood. Herein it was shown that liraglutide confers vaso- and cardioprotective effects in a non-diabetic murine model of Angiotensin II (ATII)-induced arterial hypertension, which rely on the antioxidant and anti-inflammatory actions of liraglutide and require the endothelial GLP-1 receptor (GLP-1R). Using C57BL/6J wild-type mice, it was demonstrated that liraglutide effectively protects from an ATII-mediated increase in blood pressure, cardiac hypertrophy, vascular fibrosis, and endothelial dysfunction – independently of alterations in insulin and glucose metabolism. Mechanistic analyses revealed that liraglutide downregulates central pro-inflammatory mediators such as nuclear factor-kB (NF-kB) and adhesion molecules (VCAM-1, vascular cell adhesion molecule 1; ICAM-1, intercellular adhesion molecule 1; P-selectin) in the vessel wall, which reduces the vascular adhesion and infiltration of inflammatory monocytes and neutrophils. As they are a main source of reactive oxygen species (ROS) with their endogenous NADPH oxidase 2 (Nox2) activity, liraglutide significantly attenuated ATII-induced vascular oxidative stress. As a result, S-glutathionylation and thus endothelial nitric oxide synthase (eNOS) uncoupling was prevented, which in turn markedly improved NO bioavailability and explains liraglutide's protection against hypertension-associated damage. Importantly, all of these effects were dependent on the canonical GLP-1R, as liraglutide no longer protected global Glp1r knockout mice (Glp1r-/-) from vascular oxidative stress, inflammation, and endothelial dysfunction. As another central aspect of this study, it was shown that liraglutide alleviates cardiovascular complications of arterial hypertension through selective action on the endothelial GLP-1R. With the use of myelomonocytic (Glp1r my-/-) and endothelial cell (Glp1r ec-/-)-specific Glp1r knockout mice, it was demonstrated that the beneficial effects of liraglutide persist upon GLP-1R deletion in inflammatory cells but are abrogated in the absence of the endothelial GLP-1R. Hence, this work revealed that the immunomodulating effect of liraglutide is not mediated by direct activation of the GLP-1R on myeloid cells but indirectly through stimulation of the endothelial GLP-1R. The here presented vascular/endothelial mechanism contributes to a better molecular understanding of the cardioprotective effects of long-acting GLP-1RAs like liraglutide reported in clinical trials and provides first evidence for a potential use of GLP-1RAs in the prevention and treatment of (cardio-)vascular disease beyond diabetes mellitus that are characterized by oxidative stress and inflammation.