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Novel Roles of Thrombospondin-1 in Vascular Physiology and Disease

Bauer, Eileen Maria (2010) Novel Roles of Thrombospondin-1 in Vascular Physiology and Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Heart disease is the leading cause of death nationwide, killing one of every four Americans in all communities. The health care costs associated with heart disease have been estimated to surpass 300 billion dollars in 2010. Various preventative risk factors have been identified like obesity, diabetes, cigarette smoking, and air pollution. Pulmonary hypertension (PH) is a common secondary pathogenesis associated with cardiovascular disease. Understanding its exact physiological mechanisms will allow for better treatment options and better ways of preventing the disease. The importance of nitric oxide (NO) in biology was recognized in 1998 when the Nobel Prize in Physiology or Medicine was awarded for its discovery as a physiologic signaling molecule and was validated again in 1992 by naming it "the molecule of the year". NO, produced in the endothelium by the enzyme nitric oxide synthase (eNOS), is critical in maintaining blood pressure by functioning as vasodilator. Its lack in the vascular system leads to problems, like heart disease and PH. As a critical signaling molecule, NO is likely to be important in transducing the effects of a broad variety of environmental stimuli on vasomotor regulation and studying the regulation of NO's biosynthetic capacity is of great public health importance. Recent studies demonstrate that the glycoprotein thrombospondin-1 (TSP1) influences vascular responses by interfering with the NO-mediated vasodilatory pathway at downstream targets. We hypothesized that TSP1 directly modulates eNOS activity and, thus, endothelium-dependent relaxation of blood vessels. Further, we were interested in how the inhibitory effects of TSP1 on eNOS would translate in a disease setting, specifically PH. This study demonstrates TSP1's negative role in the protective NO-mediated vasodilatory pathway and establishes a clear role for TSP1 in the development of PH. Despite the advent of several new drugs for the treatment of PH mortality remains high. Importantly, these drugs aim at increasing NO's bioavailability. The studies described herein suggest that increased TSP1 expression may limit the efficacy of these drugs. A deeper understanding of the role of TSP1 in physiology and disease will open new avenues in our fight to prevent heart disease.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bauer, Eileen Mariaeileen.bauer@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPitt, Brucebrucep@pitt.eduBRUCEP
Committee MemberBarchowsky, Aaronaab20@pitt.eduAAB20
Committee MemberO'Donnell, Chrisodonnellcp@upmc.eduCPO2
Committee MemberSt Croix, Claudettecls13@pitt.eduCLS13
Committee MemberIsenberg, Jeffjsi5@pitt.eduJSI5
Date: 28 June 2010
Date Type: Completion
Defense Date: 7 April 2010
Approval Date: 28 June 2010
Submission Date: 11 April 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: akt; caveolin; eNOS uncoupling
Other ID: http://etd.library.pitt.edu/ETD/available/etd-04112010-103246/, etd-04112010-103246
Date Deposited: 10 Nov 2011 19:35
Last Modified: 19 Dec 2016 14:35
URI: http://d-scholarship.pitt.edu/id/eprint/7017

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