Effects of the glucagon like-peptide-1 (GLP-1) receptor on vascular function, inflammation and thrombocyte reactivity in angiotensin-II induced arterial hypertension

心血管疾病是世界范围内死亡的主要原因。在过去的几十年里，研究确定了几个典型的风险因素，如吸烟、肥胖和动脉高血压。高血压与内皮功能密切相关。正常血管内皮通过内皮NO合酶（eNOS）释放一氧化氮（NO），一氧化氮具有血管扩张剂的作用，对血小板有抑制作用。内皮功能障碍被证明是人类未来心血管事件的一个指标，并与一氧化氮生物利用度降低有关。一方面，后者依赖于功能失调的eNOS（酶的解偶联），另一方面，氧化应激增加，这代表了NO的汇。众所周知，动脉高血压是一种慢性炎症性疾病，其中炎症细胞（骨髓单核细胞）向血管壁浸润起主要作用。这种现象是由功能失调（激活）的内皮细胞引发的，并进一步增加血管氧化应激，导致恶性循环。除了炎症细胞外，血栓细胞也有助于内皮功能障碍。研究表明，在动脉性高血压动物模型中，血栓细胞反应过度，产生更多的凝血酶。胰高血糖素样肽-1 （GLP-1）是一种已知具有抗炎特性的肽激素。它增加胰腺β细胞的胰岛素释放，其合成类似物用于治疗2型糖尿病。在我们小组之前的工作中，我们发现GLP-1可以改善脓毒性休克动物的生存，同时改善血管功能，抑制氧化应激和炎症。此外，我们的研究表明，GLP-1对实验性脓毒症中的炎症细胞（骨髓单核细胞）和血小板有抑制作用。在初步实验中，我们可以证明血管炎症和氧化应激减少，内皮功能在动脉高血压动物模型中得到改善。本研究旨在探讨GLP-1对高血压模型血管功能、氧化应激、炎症和血栓细胞反应性的有益作用。为了获得更多的机制，将使用内皮细胞、骨髓单核细胞和血小板中GLP-1受体的细胞特异性敲除小鼠。本研究包括翻译方法，其中GLP-1信号传导和动脉高血压患者的内皮功能将被研究。

Cardiovascular disease are a leading cause of death worldwide. Within the last decades research identified several classical risk factors, like smoking, obesity and arterial hypertension. Arterial hypertension and endothelial function build a close relationship. A normal vascular endothelium releases nitric oxide (NO) by the endothelial NO synthase (eNOS), which acts as a vasodilator and has inhibitory effects on thrombocytes. Endothelial dysfunction was shown to be an indicator for future cardiovascular events in humans and is associated with reduced NO bioavailability. On the one hand the latter relies on a dysfunctional eNOS (uncoupling of the enzyme) and on the other hand increased oxidative stress, which represents a sink for NO. Arterial hypertension is known to be a chronic inflammatory disease, in which infiltration of inflammatory cells (myelomonocytic cells) into the vascular wall plays a major role. This phenomenon is triggered by a dysfunctional (activated) endothelium and further increases vascular oxidative stress resulting in a vicious circle. Besides inflammatory cells, also thrombocytes contribute to endothelial dysfunction. It has been shown, that thrombocytes are hyper-reactive and generate more thrombin in animal models of arterial hypertension.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. In a previous work of our group it was shown that GLP-1 improves survival of animals with septic shock, which was accompanied by improved vascular function as well as suppressed oxidative stress and inflammation. Furthermore, our studies demonstrated that GLP-1 has inhibitory effects on inflammatory cells (myelomonocytes) and thrombocytes in experimental sepsis. In preliminary experiments we could demonstrate that vascular inflammation and oxidative stress were reduced, endothelial function was improved in an animal model of arterial hypertension. The aim of the present study is to investigate beneficial effects of GLP-1 on vascular function, oxidative stress, inflammation and thrombocyte reactivity in models of arterial hypertension. In order to obtain more mechanistic insight, cell-specific knockout mice for GLP-1 receptor in endothelial cells, myelomonocytes and thrombocytes will be used. The present study includes a translational approach, in which GLP-1 signaling and endothelial function of patients with arterial hypertension will be investigated.