Pleiotropic Role of PAI-1 in Cardiovascular Aging

PAI-1 在心血管衰老中的多效作用

• 批准号: 10736157
• 负责人: Douglas E Vaughan
• 金额: $ 71.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10736157
• 关键词: Adult; Age; Aging; Alleles; Alzheimer' s Disease; American; Amish; Back; Biological Aging; Blood Vessels; Brain; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Cells; Communities; Coronary Arteriosclerosis; DNA Methylation; Development; Diabetes Mellitus; Disease; Disease susceptibility; Echocardiography; Electrocardiogram; Endothelium; Enrollment; Epigenetic Process; Fasting; Female; Gene Proteins; Generations; Genetic; Genotype; Geography; Geroscience; Heart; Heart failure; Heterozygote; Human; Hypertension; In Vitro; Indiana; Individual; Insulin; Investigation; Kidney; Knock-out; Laboratories; Lead; Link; Longevity; Lung; Mediator; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Mutation; Natural experiment; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obstructive Lung Diseases; Outcome; Pathology; Phenotype; Physiologic pulse; Physiological; Physiology; Plasma; Plasminogen; Plasminogen Activator Inhibitor 1; Population; Premature aging syndrome; Prevalence; Privatization; Process; Proteins; Pulmonary Emphysema; Pulse Pressure; Reporting; Resistance; Risk Factors; Role; SERPINE1 gene; Science; Skin; Smooth Muscle Myocytes; System; Testing; Therapeutic; Therapeutic Intervention; Thrombosis; Time; Tissues; Translating; Variant; Vascular Smooth Muscle; body system; cardiovascular risk factor; cohort; comorbidity; design; endothelial dysfunction; epigenomic profiling; experimental study; fatty liver disease; flexibility; genetic variant; heart rate variability; human old age (65+); in vivo; induced pluripotent stem cell; kindred; lifestyle intervention; loss of function; loss of function mutation; multidisciplinary; multiple chronic conditions; mutation carrier; novel; null mutation; pharmacologic; pleiotropism; preservation; prevent; protective effect; reparative capacity; resilience; senescence; stressor; telomere

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

总结。65岁以上的美国人数量正在增长，预计将从

项目成果

PAI-1 is a critical regulator of FGF23 homeostasis.

• DOI: 10.1126/sciadv.1603259
• 发表时间: 2017-09
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Eren M;Place AT;Thomas PM;Flevaris P;Miyata T;Vaughan DE
• 通讯作者: Vaughan DE

PAI-1 in tissue fibrosis.

• DOI: 10.1002/jcp.22783
• 发表时间: 2012-02
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Ghosh, Asish K.;Vaughan, Douglas E.
• 通讯作者: Vaughan, Douglas E.

PAI-1 antagonists: the promise and the peril.

• 发表时间: 2011
• 期刊: Transactions of the American Clinical and Climatological Association
• 作者: D. Vaughan

A null mutation in SERPINE1 protects against biological aging in humans.

• DOI: 10.1126/sciadv.aao1617
• 发表时间: 2017-11
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Khan SS;Shah SJ;Klyachko E;Baldridge AS;Eren M;Place AT;Aviv A;Puterman E;Lloyd-Jones DM;Heiman M;Miyata T;Gupta S;Shapiro AD;Vaughan DE
• 通讯作者: Vaughan DE

Role of PAI-1 in hepatic steatosis and dyslipidemia.

• DOI: 10.1038/s41598-020-79948-x
• 发表时间: 2021-01-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Levine JA;Oleaga C;Eren M;Amaral AP;Shang M;Lux E;Khan SS;Shah SJ;Omura Y;Pamir N;Hay J;Barish G;Miyata T;Tavori H;Fazio S;Vaughan DE
• 通讯作者: Vaughan DE