Pleiotropic Role of PAI-1 in Cardiovascular Aging

摘要65岁以上的美国人数量正在增长，预计将从2015年的1.5亿人增加到2016年的1.5亿人。 2010年约为3900万，到2030年估计为7100万。多种发病率，包括 心血管疾病、阿尔茨海默氏痴呆症、肺气肿和糖尿病的发病率随着年龄的增长而显著增加。一 最有效的老化和衰老的分子指纹是蛋白质纤溶酶原激活物抑制剂- 1（派-1）（SERPINE 1基因的蛋白产物）。一个非常强大和一致的实验机构， 来自世界各地的实验室产生的证据已经确定了派-1和 在每一个主要器官系统，包括心脏、肾脏和皮肤等，都存在类似衰老的病理学。健康 在人类群体中，派-1水平较高与冠状动脉疾病、血管紧张素转换酶抑制剂增加、 僵硬、肥胖、糖尿病、脂肪肝和肺气肿/阻塞性肺病。派-1 派-1的缺乏和/或药理学抑制提供了对抗衰老样的实质性保护 心血管病理学。派-1缺乏对生物衰老的保护作用似乎是 在人类中运作。在一个地理和遗传限制的旧秩序阿米什社区， 非凡的“自然”实验已经进行了8代。这个社区有一个私人的损失- SERPINE 1中的LOF突变，可以追溯到一个单一的祖先， 在19世纪后期的社区。SERPINE 1无效突变的杂合子携带者 更长的端粒，更低的空腹胰岛素水平，保护糖尿病，保持血管的灵活性，以及更长的 寿命比他们未受影响的亲属。在这项提案中，我们将测试终身派-1缺乏的假设， 提供多方面的保护，防止心血管老化。此应用程序旨在调查 派-1对心血管弹性和衰老的多效性作用，并揭示了 解释这些影响。这些研究将利用世界上唯一已知的具有自然发生的 派-1中的功能丧失变体，在小鼠和iPSC衍生的血管细胞中进行实验研究， 这些发现的普遍性。我们预计，这里提出的研究将推动我们的 了解派-1在衰老相关心血管疾病中的关键作用， 这解释了这种关系，并提供了原则证据，即派-1的药理学抑制是合理的， 预防人类衰老相关多发病的治疗方法

SUMMARY. The number of Americans over age 65 years is growing and is projected to increase from approximately 39 million in 2010 to an estimated 71 million in 2030. The prevalence of multi-morbidity, including cardiovascular disease, Alzheimer's dementia, emphysema, and diabetes increases significantly with age. One of the best validated molecular fingerprints of aging and senescence is the protein plasminogen activatorinhibitor- 1 (PAI-1) (the protein product of the gene SERPINE1). A remarkably robust and consistent body of experimental evidence generated by laboratories from around the world have identified a mechanistic link between PAI-1 and aging-like pathology in every major organ system, including the heart, kidney and skin among others. In healthy human populations, higher levels of PAI-1 are associated with coronary artery disease, increased vascular stiffness, obesity, diabetes, fatty liver disease, and emphysema/obstructive lung disease. Conversely, PAI-1 deficiency and/or pharmacological inhibition of PAI-1 provides substantial protection against aging-like cardiovascular pathology in mice. The protective effect of PAI-1 deficiency on biological aging appears to be operational in humans. In a geographically and genetically constrained community of Old Order Amish, a remarkable “natural” experiment has been underway for 8 generations. This community harbors a private loss- of-function (LOF) mutation in SERPINE1, that can be traced back to a single ancestor that married into the community in the late part of the 19th century. Heterozygous carriers of the null mutation in SERPINE1 have longer telomeres, lower fasting insulin levels, protection from diabetes, preserved vascular flexibility, and a longer life span than their unaffected kindred. In this proposal, we will test the hypothesis that lifelong PAI-1 deficiency provides multifaceted protection against cardiovascular aging. This application is designed to investigate the pleiotropic effects of PAI-1 on cardiovascular resilience and aging and reveal the molecular mechanisms that explain these effects. These studies will leverage the only known kindred in the world with a naturally occurring loss-of-function variants in PAI-1 with experimental studies in mice and in iPSC-derived vascular cells to translate the generalizability of these findings. We anticipate that the studies proposed here will advance our understanding of the pivotal role of PAI-1 in aging-related cardiovascular disease, the molecular mechanisms that explain this relationship, and provide proof of principle that pharmacological inhibition of PAI-1 is a rational therapeutic approach in preventing aging-related multi-morbidity in humans