DISTINCT HUMAN MACROPHAGE RECEPTOR FOR ABNORMAL VLDL

由于动脉粥样硬化引起的心血管疾病（CVD）是心血管疾病的主要原因。 死亡在美国。单核细胞-巨噬细胞（MM）衍生的脂质填充“泡沫 “细胞”是早期脂肪条纹和后期容易破裂的标志， 血栓形成性病变血浆甘油三酯升高[高（H）TG，空腹 或餐后]是动脉粥样硬化血栓形成疾病的新兴风险因素; 机械连接是未知的。一种可能的机制是通过MM 我们鉴定了一种与富含TG的脂蛋白的apoB结合的受体（R （TGRLP），包括乳糜微粒（CM）的apoB-48，诱导 与动脉粥样硬化病变和骨中的体内类似 骨髓、皮肤和脾脏中的持续CM和残留物。我们 克隆了人R的cDNA（3773 bp）。它编码了一个新的，独特的R， 诱导TGRLP摄取和泡沫细胞形成时，转染到R- 阴性CHO-K1细胞。其约3.8kb的mRNA在THP-1中表达， 单核细胞，胎盘，外周单核白细胞，骨髓， 脾脏、扁桃体、淋巴结和阑尾，像泡沫一样分布 在患有持续性CM的人体内进行体内细胞培养。免疫组织化学研究 显示人主动脉脂肪条纹泡沫细胞中R表达，晚期 冠状动脉和颈动脉病变以及免疫组织的MM。我们假设 受体正常作用是确保必需的 膳食脂质和脂溶性维生素的单核细胞和可获得的 免疫系统的巨噬细胞;当不堪重负时，如在 持续性CM，它参与泡沫细胞形成和动脉粥样硬化形成。 为了在体内验证这一假设， 胚胎干细胞（ES细胞）将被用于使R缺陷（R-/-和R-/+） 小鼠和组织特异性、过表达转基因动物。基因的影响 剂量对脂蛋白谱和动脉粥样硬化易感性的影响 以及与动脉粥样硬化小鼠模型（apoE-/-，LDLR-/-）的交叉试验 和HTG（apoCIII和apoCI转基因）将有助于阐明这种R的作用 在体内脂蛋白代谢和动脉粥样硬化形成中。体外研究 单核细胞和转染的CHO将定义R的机制， 核心脂质的合成、加工、循环和摄取。的潜在 这种R对CVD的影响保证了所提出的研究提供细胞， 分子和体内功能原理， 干预措施。

Cardiovascular disease (CVD) due to atherosclerosis is the major cause of death on the US. Monocyte-macrophage (MM)-derived, lipid-filled "foam cells" are hallmarks of both early fatty streak and later, rupture-prone, thrombogenic lesions. Elevated plasma triglycerides [hyper (H) TG, fasting or post-prandial] are emerging risk factors for atherothrombotic disease; the mechanistic links are not known. One potential mechanism is via a MM receptor (R) we identified that binds apoB of TG-rich lipoproteins (TGRLP), including apoB-48 of chylomicrons (CM), inducing foam cells in vitro like those in vivo in atherosclerotic lesions and in the bone marrow, skin, and spleen in humans with persistent CMs and remnants. We have cloned the human R's cDNA (3773 bp). It encodes a new, unique R that induces TGRLP uptake and foam cell formation when transfected into R- negative CHO-K1 cells. Its approximately 3.8 kb mRNA is expressed in THP-1 monocytes, placenta, peripheral mononuclear leukocytes, bone marrow, spleen, tonsil, lymph node, and appendix, a distribution like that of foam cells in vivo in humans with persistent CMs. Immunohistochemical studies show R expression in foam cells of human aortic fatty streaks, advanced coronary and carotid lesions and MM of immune tissues. We hypothesize that the receptor's normal role is to ensure efficient delivery of essential dietary lipids and lipid-soluble vitamins to monocytes and accessible macrophages of the immune system; when overwhelmed, as in states with persistent CMs, it is involved in foam cell formation and atherogenesis. To test this hypothesis in vivo, homologous recombination in murine embryonic stem (ES) cells will be used to make R deficient (R-/- and R-/+) mice and tissue specific, over-expressing transgenics. Effects of gene dosage on lipoprotein profiles and atherosclerosis susceptibility in these and in crosses with murine models of atherosclerosis (apoE-/-, LDLR-/-) and HTG (apoCIII, and apoCI transgenics) will help clarify this R's role in lipoprotein metabolism and atherogenesis in vivo. Studies in vitro in monocytes and transfected CHOs will define mechanisms of the R's synthesis, processing, cycling, and uptake of core lipids. The potential impact of this R on CVD warrants the proposed studies to provide cellular, molecular, and in vivo functional rationales for therapeutic interventions.