Does neuropeptide Y (NPY) promote atherosclerosis?

描述（由申请人提供）：在上一个授权期，我们发现神经肽Y（NPY），一种交感神经共递质，当应用于正常血脂大鼠血管成形术损伤的颈动脉侧时，导致血管快速闭塞，新生内膜血管化，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的作用被NPY受体（R）拮抗剂（Y1和Y 5）阻止，并且在与应激产生的浓度相似的浓度下发生。血管成形术单独上调血管表达的NPY Rs。NPY刺激血管平滑肌细胞（VSMC）收缩和增殖、血管生成，引起肥胖和肥胖症，并且还是血小板衍生因子和免疫调节剂。最近，一个共同的Leu 7/Pro7-NPY信号肽基因多态性在欧洲人，产生更多的释放肽，被发现与增加总胆固醇和LDL胆固醇和加速动脉粥样硬化。考虑到这些趋同的基础和临床数据，我们现在试图确定1/3”NPY促进动脉粥样硬化，如果是这样，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动脉粥样硬化。内源性NPY及其特异性Rs的作用将在i）过表达NPY（NPY-Tg）的大鼠; ii）无NPY、Y1、Y 5或YI+ Y 5 R的小鼠; iii）具有和不具有血小板NPY过表达的小鼠，和4）用NPY R拮抗剂治疗的ApoE-/-小鼠中使用喂食高脂肪饮食且有或无血管成形术的动物来确定。AIM旨在测试1）NPY及其特异性Rs是否增加新生内膜形成和动脉粥样硬化; 2）血小板衍生的NPY是否增强血小板聚集性以及VSMC收缩和生长; 3）NPY是否刺激巨噬细胞迁移、脂质摄取、脂蛋白脂肪酶活性和泡沫细胞形成;以及4）YI-Y 5 R寡聚化是否调节NPY的受体特性，并因此调节促动脉粥样硬化作用。为了将这些数据与人类相关联，还将在人类动脉粥样硬化和非动脉粥样硬化血管中研究Leu 7/Pro7多态性与血管NPY R表达和动脉粥样硬化的关联。

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.