The average age of the U.S. population continues to increase, causing a surge in the size of the geriatric population. While only 13% of US population is 65 and older, they consume over 36% of personal health expenditures. Cardiovascular disease (CVD) is a major contributor to both mortality and health care costs among elderly population. It is becoming evident that aging results in well-defined structural and functional changes in the blood vessel wall that render the cardiovascular system prone to disease even in the absence of traditional risk factors. Moreover, age-related alterations render the aged vasculature more susceptible to the damaging effects of the common CV risk factors. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging includes endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Recent findings suggest that age-related diseases could be delayed by modulating senescence.
The Specific Aims of this proposal are designed to test the hypothesis that PAI-1 plays a critical role in the development of vascular senescence and physiological aging. Preliminary data presented here indicate that PAI-1 is not merely a marker of senescence but directly contributes to the molecular pathogenesis of senescence and aging in the cardiovascular system. We propose to use aging animals with global, as well as tissue- and function-specific PAI-1 deficiency, to delineate the involvement of PAI-1 in the age-related vascular remodeling. We will also address the effect of PAI-1 deficiency over the lifespan on the aging and senescence in a human population. We propose to study the Berne Amish community in Indiana, in which one of only 3 confirmed genetic defects associated with complete PAI-1 deficiency has been described. We anticipate that these studies will not only establish the role of PAI-1 in senescence, but will also advance our knowledge of the mechanisms that drive physiological aging. Furthermore, understanding the molecular mechanism of PAI-1's role in senescence and aging may provide new insights into the prevention and treatment of aging-related dysfunction and frailty.

Public Health Relevance

Cardiovascular disease (CVD) is a major contributor to both mortality and health care costs among elderly population. It is becoming evident that aging results in well-defined structural and functional changes in the blood vessel wall that render the cardiovascular system prone to disease even in the absence of traditional risk factors. In this proposal, we will test a novel hypothesis that genetic deficiency of PAI-1 protects against vascular senescence and aging. We anticipate that animal and human studies proposed here will establish the pivotal role of PAI-1 in vascular senescence and provide new insights into the prevention and treatment of aging-related dysfunction and frailty.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01HL051387-18A1
Application #
8696950
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Eren, Mesut; Boe, Amanda E; Murphy, Sheila B et al. (2014) PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci U S A 111:7090-5
Ghosh, Asish K; Quaggin, Susan E; Vaughan, Douglas E (2013) Molecular basis of organ fibrosis: potential therapeutic approaches. Exp Biol Med (Maywood) 238:461-81
Rose, Shawn; Eren, Mesut; Murphy, Sheila et al. (2013) A novel mouse model that develops spontaneous arthritis and is predisposed towards atherosclerosis. Ann Rheum Dis 72:89-95
Boe, Amanda E; Eren, Mesut; Murphy, Sheila B et al. (2013) Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nýý-nitro-L-arginine methyl ester-induced hypertension and vascular senescence. Circulation 128:2318-24
Ghosh, Asish K; Murphy, Sheila B; Kishore, Raj et al. (2013) Global gene expression profiling in PAI-1 knockout murine heart and kidney: molecular basis of cardiac-selective fibrosis. PLoS One 8:e63825
Lee, Sun H; Eren, Mesut; Vaughan, Douglas E et al. (2012) A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma. Am J Respir Cell Mol Biol 46:842-6
Ghosh, Asish K; Nagpal, Varun; Covington, Joseph W et al. (2012) Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differential expression of microRNAs during EndMT. Cell Signal 24:1031-6
Ghosh, Asish K; Vaughan, Douglas E (2012) PAI-1 in tissue fibrosis. J Cell Physiol 227:493-507
Vaughan, Douglas E (2011) PAI-1 antagonists: the promise and the peril. Trans Am Clin Climatol Assoc 122:312-25
Meadows, Judith L; Vaughan, Douglas E (2011) Endothelial biology in the post-menopausal obese woman. Maturitas 69:120-5

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