Does neuropeptide Y (NPY) promote atherosclerosis?

描述(申请人提供)：在之前的资助期间，我们发现神经肽Y(NPY)是一种交感神经共同递质，应用于正常血压大鼠血管成形术损伤的颈动脉一侧时，可导致血管新生内膜快速闭塞，含有基质、血栓、巨噬细胞和脂质，类似于晚期动脉粥样硬化病变。NPY的作用可被NPY受体(R)拮抗剂(Y1和Y5)阻止，并且在与应激产生的浓度相似的浓度下发生。单纯血管成形术可上调血管NPY受体的表达。NPY可刺激血管平滑肌细胞(VSMC)收缩和增殖，促进血管生成，引起肥胖和高脂血症，也是一种血小板衍生因子和免疫调节剂。最近，欧洲人常见的Leu7/Pro7-NPY信号肽基因多态性，产生一种更易释放的多肽，被发现与总胆固醇和低密度脂蛋白胆固醇增加以及加速的动脉粥样硬化有关。考虑到这些趋同的基础和临床数据，我们现在试图确定/3“NPY促进动脉粥样硬化，如果是的话，是通过什么机制。我们假设NPY通过刺激动脉粥样硬化的几个步骤而促进动脉粥样硬化。内源性NPY及其特异性受体的作用将通过喂饲高脂饮食并进行血管成形术的动物来确定，这些动物包括：i)高表达NPY的大鼠(NPY-TG)；ii)NPY、Y1、Y5或Y1 Y5 R缺失的小鼠；iii)血小板NPY高表达或不高表达的小鼠；以及4)用NPY R拮抗剂治疗的ApoE-/-小鼠。目的是测试1)NPY及其特异性受体是否增加新生内膜形成和动脉粥样硬化；2)血小板来源的NPY增加血小板聚集性，以及VSMC的收缩和生长；3)NPY刺激巨噬细胞迁移、脂质摄取、脂蛋白脂肪酶活性和泡沫细胞形成；4)YI-Y5R寡聚调节NPY的受体特性，从而促进动脉粥样硬化的作用。为了将这些数据与人类联系起来，还将在人类动脉粥样硬化和非动脉粥样硬化的血管中研究Leu7/Pro7多态与血管NPY R表达和动脉粥样硬化的关系。

DESCRIPTION (provided by applicant): In the previous grant period, we discovered that neuropeptide Y (NPY), a sympathetic co-transmitter, when applied at the side of angioplasty-injured carotid artery in normolipemic rats, leads to fast vessel occlusion with vascularized neointima, containing matrix, thrombus, macrophages and lipids, and resembling advanced atherosclerotic lesion. NPY's effect is prevented by NPY receptor (R) antagonists (Y1 and Y5) and occurs at concentrations similar to those yielded by stress. Angioplasty alone up-regulates vascular expression of NPY Rs. NPY stimulates vascular smooth muscle cell (VSMC) contraction and proliferation, angiogenesis, causes obesity and hyperlipemia, and is also a platelet-derived factor and immunomodulator. Recently, a common Leu7/Pro7-NPY signal peptide gene polymorphism in Europeans, producing a more releasable peptide, is found to associate with increased total and LDL cholesterol and accelerated atherosclerosis. Considering these convergent basic and clinical data, we now seek to determine/3" NPYpromotes atherosclerosis, and if so, by what mechanisms. We hypothesize that NPY is pro-atherosclerotic by stimulating several steps of atherosclerosis. The role of endogenous NPY and its specific Rs will be determined using animals fed high fat diet with or without angioplasty in i) rats over-expressing NPY (NPY-Tg); ii) mice null for NPY, Y1, Y5 or YI+Y5 R; iii) mice with and without platelet NPY over-expression, and 4) ApoE-/- mice treated with NPY R antagonists. AIMs are to test if 1) NPY and its specific Rs increase neointima formation and atherosclerosis; 2) platelet-derived NPY augments platelet aggregability, and VSMC contraction and growth; 3) NPY stimulates macrophage migration, lipid uptake, lipoprotein lipase activity and foam cell formation; and 4) YI-Y5R oligomerization regulates NPY's receptor properties and, hence, pro-atherosclerotic actions. To relate these data to humans, the association of the Leu7/Pro7 polymorphism with vascular NPY R expression and atherosclerosis will also be studied in human atherosclerotic and non-atherosclerotic vessels.