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New mechanisms in nitric oxide synthase related endothelial dysfunction in the isolated heart

Reyes, Levy Austin
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338346540

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Induction of ischemia/reperfusion (IR) injury has been shown to render endothelial nitric oxide synthase (eNOS) dysfunctional; limiting the endogenous mechanisms which regulate vasodilation in the vessel. In the heart, this results in limited tissue perfusion via coronary arteries, which when persistent, results in pump failure. Recently it has been shown that in the ex vivo, isolated heart model, IR results in depletion of the critical NOS cofactor, tetrahydrobiopterin (BH4). When the lost eNOS cofactor is repleted the activity of the dysfunctional enzyme can be partially ameliorated and vasodilation, while incomplete, is markedly improved. The lack of complete restoration in vasodilation led to this thesis work, which sought to explore the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH), a critical NOS substrate, in enzymatic function after IR injury. The levels of all pyridine nucleotides where measured throughout ischemia, and subsequent reperfusion to determine any fluctuations in levels as a result of the injurious stimuli. It was found that within the whole-heart, the levels of both NADPH and NADP+ (oxidized form of NADPH) were depleted during reperfusion. Furthermore, this depletion appears to be targeted to the endothelium, where the degree of NADP(H) depletion was most severe. Repletion of lost NADPH after IR resulted in a robust increase in coronary flow, when repletion of NADPH was performed with the addition of the eNOS inhibitor, L-NAME, these benefits were lost. Furthermore, repletion of NADPH was vastly superior to BH4 repletion, but when given together the improvement to coronary flow was cumulative. In our model of the isolated heart we show the decline of NADP+ coincides with the production of 2’-phospho-cyclic ADP-ribose (2’-P-cADPR), a signaling molecule produced from the ADP-ribosyl cyclase activity of CD38. Originally identified as an antigen marker on B-Cells, CD38 was later found to contain sequence homology with ADP-ribosyl cyclase. It has been widely reported that CD38 activity increases with IR, however these reports only describe this increase in activity as an increase in cADPR, the NAD+ analogue, which also has been described as a Ca2+ mobilizing agent. Here we show that activity of CD38 from isolated hearts subjected to IR resulted in an increase of 2’-P-cADPR which was 5x that of basal levels. The interaction between CD38 and eNOS was evident when inhibitors to CD38 prevented endothelial loss of NADP(H) and resulted in improved NOS dependent coronary flow over untreated isolated hearts. This link offers a new therapeutic option which could result in improved coronary flow in the face of IR injury.
Jay L. Zweier, MD (Advisor)
Mark T. Ziolo, PhD (Committee Member)
Richard J. Gumina, MD, PhD (Committee Member)
Arthur R. Strauch, PhD (Committee Member)
149 p.
Biomedical Research
NADPH; eNOS; CD38; 2'-P-cADPR; ischemia/reperfusion injury; myocardial infarction; isolated heart; glutathiolynation

Recommended Citations

Citations

  • Reyes, L. A. (2012). New mechanisms in nitric oxide synthase related endothelial dysfunction in the isolated heart [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338346540

    APA Style (7th edition)

  • Reyes, Levy. New mechanisms in nitric oxide synthase related endothelial dysfunction in the isolated heart. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1338346540.

    MLA Style (8th edition)

  • Reyes, Levy. "New mechanisms in nitric oxide synthase related endothelial dysfunction in the isolated heart." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338346540

    Chicago Manual of Style (17th edition)

osu1338346540
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.