APOLIPOPROTEIN CELLULAR INTERACTIONS IN VASCULAR BIOLOGY

低脂高密度脂蛋白与载脂蛋白的相互作用，细胞通过一种名为ABC1的ABC转运蛋白控制的依赖高尔基体的活性途径刺激过量胆固醇的分泌。这一途径产生含有脂质和细胞囊泡运输蛋白(如β-COP)的颗粒，并似乎依赖于细胞蛋白多糖。分泌的含有β-COP的颗粒与结合肝素的血浆高密度脂蛋白相关。因此，缺乏脂质的载脂蛋白通过复杂的分泌途径去除细胞内的脂质和蛋白质，该途径产生的颗粒可能会瞬时结合到动脉基质蛋白多糖上。我们的假设是，载脂蛋白与动脉细胞的相互作用通过多种机制保护动脉粥样硬化，包括清除细胞内多余的胆固醇和产生干扰致动脉脂蛋白与动脉蛋白多糖结合的颗粒。我们将定义成纤维细胞、培养的动脉平滑肌细胞和巨噬细胞中载脂蛋白介导的分泌途径的生化和形态特征，并描述在这些不同的细胞中调节这一途径的因素。我们还将进行研究，以确定和表征在这些不同细胞中调节这一途径的细胞蛋白和蛋白多糖。我们还将进行研究，以确定和表征受细胞载脂蛋白相互作用调节、运输和/或分泌的细胞蛋白和蛋白多糖。最后，我们将表征分泌和血浆中的含有βCOP的颗粒与蛋白多糖的结合，并鉴定含有βCOP的颗粒中的肝素和蛋白多糖结合蛋白(S)。这些研究将更详细地确定载脂蛋白介导的动脉壁细胞分泌途径的特性，并为该途径保护动脉粥样硬化的机制提供更多的见解。对高密度脂蛋白抗动脉粥样硬化作用的细胞和细胞外机制的了解可能提示，高密度脂蛋白抗动脉粥样硬化作用的细胞外机制可能为预防和逆转心血管疾病提供治疗干预措施。

The interaction of lipid-poor HDL apolipoproteins which cells stimulates secretion of excess cholesterol by an active Golgi-dependent pathway controlled by an ABC transporter called ABC1. This pathway generates particles containing lipids and cellular vesicular transport proteins such as betaCOP and appears to depend on cellular proteoglycans. The secreted betaCOP-containing particles become associated with a subst of plasma HDL that binds heparin. Thus, lipid-poor apolipoproteins remove cellular lipids and proteins by a complex secretory pathway that generates particles that may transiently bind to arterial matrix proteoglycans. Our hypothesis is that the interaction of apolipoproteins with arterial cells protects against atherosclerosis by multiple mechanisms, including removing excess cellular cholesterol and producing particles that interfere with binding of atherogenic lipoproteins to arterial proteoglycans. We will define the biochemical and morphological properties of the apolipoprotein-mediated secretory pathway in fibroblast, cultured arterial smooth muscle cells, and macrophages, and we will characterize factors that regulate this pathway in these different cells. We will also conduct studies to identify and characterize cellular proteins and proteoglycans that regulate this pathway in these different cells. We will also conduct studies to identify and characterize cellular proteins and proteoglycans that are regulated., transported, and/or secreted in response to cellular apolipoprotein interactions. Lastly, we will characterize the binding of secreted and plasma betaCOP-containing particles to proteoglycans and identify the heparin and proteoglycan binding protein(s) in betaCOP- containing particles. These studies will define in more detail the properties of the apolipoprotein-mediated secretory pathway in arterial wall cells and provide more insight into mechanisms by which this pathway protects against atherosclerotic. An understanding of the cellular and extracellular mechanisms that underlie the anti-atherogenic effects of HDL apolipoproteins may suggest extracellular mechanisms that underlie the anti-atherogenic effects of HDL apolipoproteins may suggest therapeutic interventions for preventing and regressing cardiovascular disease.