OBJECTIVE Cardiovascular outcome trials demonstrated that GLP-1 (glucagon-like peptide-1) analogs including liraglutide reduce the risk of cardiovascular events in type 2 diabetes mellitus. Whether GLP-1 analogs reduce the risk for atherosclerosis independent of glycemic control is challenging to elucidate as the GLP-1R (GLP-1 receptor) is expressed on different cell types, including endothelial and immune cells. Approach and Results: Here, we reveal the cardio- and vasoprotective mechanism of the GLP-1 analog liraglutide at the cellular level in a murine, nondiabetic model of arterial hypertension. Wild-type (C57BL/6J), global (Glp1r-/-), as well as endothelial (Glp1rflox/floxxCdh5cre) and myeloid cell-specific knockout mice (Glp1rflox/floxxLysMcre) of the GLP-1R were studied, and arterial hypertension was induced by angiotensin II. Liraglutide treatment normalized blood pressure, cardiac hypertrophy, vascular fibrosis, endothelial dysfunction, oxidative stress, and vascular inflammation in a GLP-1R-dependent manner. Mechanistically, liraglutide reduced leukocyte rolling on the endothelium and infiltration of myeloid Ly6G-Ly6C+ and Ly6G+Ly6C+ cells into the vascular wall. As a consequence, liraglutide prevented vascular oxidative stress, reduced S-glutathionylation as a marker of eNOS (endothelial NO synthase) uncoupling, and increased NO bioavailability. Importantly, all of these beneficial cardiovascular effects of liraglutide persisted in myeloid cell GLP-1R-deficient (Glp1rflox/floxxLysMcre) mice but were abolished in global (Glp1r-/-) and endothelial cell-specific (Glp1rflox/floxxCdh5cre) GLP-1R knockout mice. CONCLUSIONS GLP-1R activation attenuates cardiovascular complications of arterial hypertension by reduction of vascular inflammation through selective actions requiring the endothelial but not the myeloid cell GLP-1R.

中文翻译：

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内皮GLP-1（胰高血糖素样肽1）受体通过利拉鲁肽介导实验性高血压小鼠的心血管保护作用。

目的心血管结果试验表明，包括利拉鲁肽在内的GLP-1（胰高血糖素样肽1）类似物可降低2型糖尿病患者发生心血管事件的风险。由于GLP-1R（GLP-1受体）在包括内皮细胞和免疫细胞在内的不同细胞类型上表达，因此要阐明GLP-1类似物是否降低血糖独立于动脉粥样硬化的风险具有挑战性。方法和结果：在这里，我们在小鼠，非糖尿病性动脉高血压模型中揭示了GLP-1类似物利拉鲁肽在细胞水平上的心脏和血管保护机制。研究了GLP-1R的野生型（C57BL / 6J），整体性（Glp1r-/-）以及内皮细胞（Glp1rflox / floxxCdh5cre）和髓样细胞特异性基因敲除小鼠（Glp1rflox / floxxLysMcre），并研究了高血压由血管紧张素II诱导。利拉鲁肽治疗以GLP-1R依赖性方式使血压，心脏肥大，血管纤维化，内皮功能障碍，氧化应激和血管炎症正常化。从机制上讲，利拉鲁肽减少白细胞在内皮上的滚动以及髓样Ly6G-Ly6C +和Ly6G + Ly6C +细胞向血管壁的浸润。结果，利拉鲁肽预防了血管氧化应激，减少了作为eNOS（内皮型NO合酶）解偶联标记的S-谷胱甘肽化作用，并提高了NO的生物利用度。重要的是，利拉鲁肽的所有这些有益的心血管作用在缺乏髓样细胞GLP-1R（Glp1rflox / floxxLysMcre）的小鼠中仍然存在，但在整体（Glp1r-/-）和内皮细胞特异性（Glp1rflox / floxxCdh5cre）GLP-1R敲除的小鼠中被废除老鼠。