Atherosclerosis: Lipoproteins, cell biology and vascular physiology

世界正面临着一种新的重大早产性心脏病流行，这种流行病是由全球肥胖率上升推动的。有几个因素导致超重和肥胖者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。另一个原因与胆固醇从动脉壁中清除的能力降低有关，因为胆固醇在动脉壁中积聚，从而导致心脏病。第三个事实是肥胖与血管慢性炎症状态有关。这种炎症不仅会加速心脏病的发展，还会使动脉中积累了胆固醇的人更有可能真正患上心脏病。第四个原因是超重和肥胖者的血管内壁功能不正常。这种正常功能的丧失是未来心脏病的非常早期的迹象。这些因素是密切相关的，“良好的”高密度脂蛋白在从动脉中去除胆固醇、抑制动脉炎症、促进正常功能和血管内膜修复方面发挥着核心作用。高密度脂蛋白是复杂的，由形状、大小和组成各不相同的几个亚群的颗粒组成。此外，这些高密度脂蛋白亚群随着它们在血液中循环，在一些血液因素的推动下不断重塑，这些因素改变了它们的大小和组成。该计划中将进行的研究的一个主要组成部分涉及了解人类血液中的高密度脂蛋白亚群是如何调节的，以及它们如何预防心脏病。申请者已经在理解“好的”高密度脂蛋白的功能、它们如何将胆固醇从动脉壁细胞中去除、它们如何抑制动脉炎症以及它们如何改善动脉衬里的功能方面做出了重大贡献。我们建议扩大这些研究，以确定如何增强这些保护功能，找出哪些高密度脂蛋白亚群最具保护性，并确定如何在心脏病风险人群中增加最具保护性的高密度脂蛋白。

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.