Atherosclerosis: Lipoproteins, cell biology and vascular physiology

世界正面临着由全球肥胖增加所导致的一种新的主要的早发性心脏病流行病。有几个因素会导致超重和肥胖人群患心脏病的风险增加。一种是血液中“有益”的高密度脂蛋白胆固醇水平较低，这种胆固醇通常可以预防心脏病。另一个原因是胆固醇从动脉壁上清除的能力下降，而动脉壁上积聚的胆固醇会导致心脏病。第三个原因是肥胖与血管的慢性炎症有关。这种炎症不仅会加速心脏病的发展，而且还会使胆固醇积聚在动脉中的人更容易心脏病发作。第四个原因是超重和肥胖人群的血管内膜不能正常运作。这种正常功能的丧失是未来心脏病的早期征兆。这些因素密切相关，“好的”高密度脂蛋白在清除动脉胆固醇、抑制动脉炎症、促进血管内膜正常功能和修复方面发挥着核心作用。高密度脂蛋白是复杂的，由几种形状、大小和成分不同的颗粒亚群的混合物组成。此外，这些高密度脂蛋白亚群在血液中循环时，在一系列血液因素的作用下不断地重塑，这些血液因素改变了它们的大小和组成。在这个项目中进行的研究的一个主要组成部分是了解人类血液中的高密度脂蛋白亚群是如何被调节的，以及它们是如何预防心脏病的。这些申请者已经在理解“好”高密度脂蛋白的功能、它们如何从动脉壁的细胞中去除胆固醇、它们如何抑制动脉炎症以及它们如何改善动脉内膜的功能方面做出了重大贡献。我们建议扩展这些研究，以确定如何增强这些保护功能，找出哪种HDL亚群最具保护作用，并确定如何在有心脏病风险的人群中增加最具保护作用的HDL。

The world is confronting a major new epidemic of premature heart disease that is being driven by a global increase in obesity. There are several factors that contribute to the increased risk of heart disease in overweight and obese people. One is a low blood level of the “good” HDL cholesterol that normally protects against heart disease. Another relates to a decreased ability to remove cholesterol from the walls of arteries where it builds up to cause heart disease. A third is the fact that obesity is associated with a state of chronic inflammation of the blood vessels. This inflammation not only accelerates the development of heart disease but also makes people who have cholesterol accumulated in their arteries more likely to actually have a heart attack. And a fourth is the fact that the lining of blood vessels does not function normally in overweight and obese people. This loss of normal function is a very early sign of future heart disease. These factors are closely inter-related, with the “good” HDL playing a central role in removing cholesterol from arteries, inhibiting arterial inflammation and promoting normal function and repair of the lining of blood vessels. HDL is complex, consisting of a mixture of several subpopulations of particles that vary in shape, size and composition. Furthermore, these HDL subpopulations are continually remodelled as they circulate in blood in reactions promoted by a number of blood factors that change their size and composition. A major component of the research to be conducted in this program relates to understanding how the HDL subpopulations in human blood are regulated and how they protect against heart disease. The applicants have already made major contributions to understanding the functions of the “good” HDLs, how they take cholesterol out of cells in the artery wall, how they inhibit inflammation of the arteries and how they improve the function of the artery lining. We propose to extend these studies to establish how these protective functions can be enhanced, to find out which of the HDL subpopulations are most protective, and to identify how to increase the most protective HDLs in people at risk of heart disease.