Indrakusuma Ira, Romacho Tania, Eckel Jürgen
Paul-Langerhans-Group for Integrative Physiology, German Diabetes Center Düsseldorf, Germany.
Paul-Langerhans-Group for Integrative Physiology, German Diabetes CenterDüsseldorf, Germany; German Center for Diabetes Research (DZD e.V.)Düsseldorf, Germany.
Front Pharmacol. 2017 Jan 4;7:497. doi: 10.3389/fphar.2016.00497. eCollection 2016.
Obesity is associated with impaired vascular function. In the cardiovascular system, protease-activated receptor 2 (PAR2) exerts multiple functions such as the control of the vascular tone. In pathological conditions, PAR2 is related to vascular inflammation. However, little is known about the impact of obesity on PAR2 in the vasculature. Therefore, we explored the role of PAR2 as a potential link between obesity and cardiovascular diseases. C57BL/6 mice were fed with either a chow or a 60% high fat diet for 24 weeks prior to isolation of aortas. Furthermore, human coronary artery endothelial cells (HCAEC) and human coronary smooth muscle cells (HCSMC) were treated with conditioned medium obtained from differentiated primary human adipocytes. To investigate receptor interaction vascular endothelial growth factor receptor 2 (VEGFR2) was blocked by exposure to calcium dobesilate and a VEGFR2 neutralization antibody, before treatment with PAR2 activating peptide. Student's -test or one-way were used to determine statistical significance. Both, high fat diet and exposure to conditioned medium increased PAR2 expression in aortas and human vascular cells, respectively. In HCSMC, conditioned medium elicited proliferation as well as cyclooxygenase 2 induction, which was suppressed by the PAR2 antagonist GB83. Specific activation of PAR2 by the PAR2 activating peptide induced proliferation and cyclooxygenase 2 expression which were abolished by blocking the VEGFR2. Additionally, treatment of HCSMC with the PAR2 activating peptide triggered VEGFR2 phosphorylation. Under obesogenic conditions, where circulating levels of pro-inflammatory adipokines are elevated, PAR2 arises as an important player linking obesity-related adipose tissue inflammation to atherogenesis. We show for the first time that the underlying mechanisms of these pro-atherogenic effects involve a potential transactivation of the VEGFR2 by PAR2.
肥胖与血管功能受损有关。在心血管系统中，蛋白酶激活受体2（PAR2）发挥多种功能，如控制血管张力。在病理条件下，PAR2与血管炎症有关。然而，关于肥胖对血管中PAR2的影响知之甚少。因此，我们探讨了PAR2作为肥胖与心血管疾病之间潜在联系的作用。在分离主动脉之前，将C57BL/6小鼠分别用普通饲料或60%高脂肪饮食喂养24周。此外，用人分化的原代脂肪细胞获得的条件培养基处理人冠状动脉内皮细胞（HCAEC）和人冠状动脉平滑肌细胞（HCSMC）。在用PAR2激活肽处理之前，通过暴露于多贝斯钙和VEGFR2中和抗体来阻断血管内皮生长因子受体2（VEGFR2），以研究受体相互作用。使用学生t检验或单因素检验来确定统计学意义。高脂肪饮食和暴露于条件培养基分别增加了主动脉和人血管细胞中PAR2的表达。在HCSMC中，条件培养基诱导增殖以及环氧合酶2的诱导，这被PAR2拮抗剂GB83抑制。PAR2激活肽对PAR2的特异性激活诱导了增殖和环氧合酶2的表达，而通过阻断VEGFR2可消除这些作用。此外，用PAR2激活肽处理HCSMC会触发VEGFR2磷酸化。在致肥胖条件下，促炎脂肪因子的循环水平升高，PAR2成为将肥胖相关的脂肪组织炎症与动脉粥样硬化联系起来的重要因素。我们首次表明，这些促动脉粥样硬化作用的潜在机制涉及PAR2对VEGFR2的潜在反式激活。
