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CD38 in the Heart: Effects of CD38 Activation on Post-Ischemic Injury

Boslett, James J
http://rave.ohiolink.edu/etdc/view?acc_num=osu1500293726035515

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Myocardial ischemia/reperfusion (I/R) is marked by a period of ischemia, the duration of which must be limited in order to prevent irreversible cell death of the affected tissue. However, the associated reperfusion (return of blood flow) has distinct mechanisms of injury separate from ischemic injury. One of these is the recently discovered mechanism by which the enzyme CD38 becomes activated as an NAD(P)+-catabolizing NAD(P)+ase, lowering cellular levels of NAD(P)(H), and affecting NAD(P)(H)-dependent cellular processes. However, little is known about the mechanistic process of CD38 activation, the affected cell types of the heart, or the therapeutic potential of blocking CD38 activation. This dissertation is comprised of four related projects that explore the phenomenon of CD38 activation in the heart. The goal of the first project was to completely characterize CD38 in the separate, main cell types of the heart. This was performed as a means to better understand CD38, generally, in the context of the whole heart. In this project, we found that CD38 is predominantly expressed in the endothelium, which made it the primary focus of the rest of this section of the dissertation, which focused on characterizing CD38 activation in the process of hypoxia/reoxygenation of endothelial cells. spectrometry approach. In this project, we found that CD38 could be immunoprecipitated from heart tissue in adequate amounts, and that certain modifications of two of CD38’s several cysteine residues could be determined. This project proved the feasibility and succeeded in the optimization of techniques capable of providing a framework for the analysis of the mechanism of CD38 activation. The third project was undertaken to determine the CD38 inhibitory effect of flavonoid luteolinidin in vitro, and then ex vivo in the isolated heart. This work provided for the first time a look at what occurs with use of a relatively potent CD38 inhibitor in the heart subjected to ischemia/reperfusion. By optimizing the delivery method and determining the dose-dependence of the cardioprotective effects, the potential for flavonoid CD38 inhibitors as therapeutics in CD38-related pathologies was evaluated. Lastly, the fourth project was designed to understand, definitively, the role of CD38 in cardiac ischemia/reperfusion by using the CD38 knockout (-/-) mouse. Experiments here built off of prior work utilizing CD38 inhibitors to provide more definitive evidence of CD38’s effects in I/R injury, without questions regarding pathway specificity. The CD38-/- mouse heart proved to be protected against I/R compared to WT hearts, confirming previous work on CD38 inhibitors in rat hearts. This chapter in particular demonstrated the need for further work on developing potent and specific CD38 inhibitors for understanding the therapeutic potential of blocking CD38 in cardiac pathologies. Research in this thesis contained many specific goals, with few broader goals. These included understanding CD38’s pattern of expression in the complex organ of the heart and characterizing CD38 activation specifically in endothelial cells, devising methodologies for analyzing changes to CD38’s molecular structure, evaluating a promising, naturally occurring CD38 inhibitor in I/R, and, lastly, definitively understanding the potential therapeutic value of blocking CD38 in cardiac ischemia/reperfusion.
Jay Zweier, Dr. (Advisor)
Jonathan Davis, Dr. (Committee Member)
Santiago Partida-Sanchez, Dr. (Committee Member)
Mark Ziolo, Dr. (Committee Member)
202 p.
Physiology

Recommended Citations

Citations

  • Boslett, J. J. (2017). CD38 in the Heart: Effects of CD38 Activation on Post-Ischemic Injury [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500293726035515

    APA Style (7th edition)

  • Boslett, James. CD38 in the Heart: Effects of CD38 Activation on Post-Ischemic Injury. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1500293726035515.

    MLA Style (8th edition)

  • Boslett, James. "CD38 in the Heart: Effects of CD38 Activation on Post-Ischemic Injury." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1500293726035515

    Chicago Manual of Style (17th edition)

osu1500293726035515
534
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This open access ETD is published by The Ohio State University and OhioLINK.