We propose to determine the role of endothelial nitric oxide synthase (eNOS) in age- or disease-related dysfunction of human endothelial progenitor cells (EPCs). One consequence of aging or accumulating different cardiovascular risk factors is a decrease in the functional capabilities of the vascular endothelium. This appears to correlate with a decrease in EPC function as measured ex vivo. Transplantation of EPCs in both animals and humans has been suggested to enhance functional tissue preservation/regeneration after myocardial infarction or peripheral ischemia, a possibly that is supported by our own preliminary studies. However, EPC function has been shown to determine the extent of tissue recovery. Decreased EPC function in culture is associated with decreased ability of EPCs to aid in tissue regeneration when transplanted after myocardial infarction. This presents the problem that ex vivo expansion and re-infusion of a patient's own EPCs may be ineffective if the EPCs themselves are functionally impaired. The main hypothesis of this proposal is that EPC function is impaired in some populations with high cardiovascular risk as a result of reduced eNOS-dependent nitric oxide (NO) production, and that dysfunctional EPCs can be functionally enhanced by engineering them to overexpress eNOS.
The specific aims are (1) to evaluate whether a correlation exists between EPC function and eNOS-dependent NO production in EPCs from populations with high versus low cardiovascular risk, including age, (2) to assess whether engineering EPCs to overexpress eNOS enhances their ability to improve function in rodent models of cardiovascular disease, and (3) to examine the mechanistic role of NO in EPC function.

Public Health Relevance

Progenitor cells that circulate in the blood are thought to participate in the growth and maintenance of blood vessels. Such progenitor cells from elderly individuals, or people who suffer from certain cardiovascular maladies, are less able to function than those from healthy young individuals. This research will determine if a deficiency in the enzyme eNOS is partially responsible for this problem, and will also explore the possibility of genetically engineering such progenitor cells to improve their function, thereby increasing their beneficial effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086917-05
Application #
8088125
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Gao, Yunling
Project Start
2007-08-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$386,250
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
An, Songtao; Wang, Xiaoyin; Ruck, Melissa A et al. (2018) Age-Related Impaired Efficacy of Bone Marrow Cell Therapy for Myocardial Infarction Reflects a Decrease in B Lymphocytes. Mol Ther 26:1685-1693
Chen, Qiumei; Varga, Monika; Wang, Xiaoyin et al. (2016) Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction. J Am Heart Assoc 5:
Aschbacher, Kirstin; Derakhshandeh, Ronak; Flores, Abdiel J et al. (2016) Circulating angiogenic cell function is inhibited by cortisol in vitro and associated with psychological stress and cortisol in vivo. Psychoneuroendocrinology 67:216-23
Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh et al. (2014) Protein engineering to develop a redox insensitive endothelial nitric oxide synthase. Redox Biol 2:156-64
Chen, Qiumei; Sievers, Richard E; Varga, Monika et al. (2013) Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo. J Appl Physiol (1985) 114:752-60
Fang, Qizhi; Mok, Pamela Y; Thomas, Anila E et al. (2013) Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants. PLoS One 8:e61413
Wang, Xiaoyin; Takagawa, Junya; Lam, Viola C et al. (2011) Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Sci Transl Med 3:100ra90
Kharait, Sourabh; Haddad, Daniel J; Springer, Matthew L (2011) Nitric oxide counters the inhibitory effects of uremic toxin indoxyl sulfate on endothelial cells by governing ERK MAP kinase and myosin light chain activation. Biochem Biophys Res Commun 409:758-63
Wang, Xiaoyin; Takagawa, Junya; Haddad, Daniel J et al. (2011) Advanced Donor Age Impairs Bone Marrow Cell Therapeutic Efficacy for Cardiac Disease. J Tissue Sci Eng S3:
Springer, Matthew L; Wang, Xiaoyin (2011) Blunting half of the double-edged sword: potential use of interleukin-10 to protect bone marrow-derived cells after myocardial infarction. Circ Res 109:1196-8

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