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Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches

Abdelghany, Tamer Mohamed Ibrahim

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Cigarette smoking (CS) remains the single largest preventable cause of death. Worldwide, smoking causes more than five million deaths annually and, according to the current trends, smoking may cause up to 10 million annual deaths by 2030. In the U.S. alone, approximately half a million adults die from smoking-related illnesses each year which represents ~ 19% of all deaths in the U.S., and among them 50,000 are killed due to exposure to secondhand smoke (SHS). Smoking is a major risk factor for cardiovascular disease (CVD). The crucial event of The CVD is the endothelial dysfunction (ED). Despite of the vast number of studies conducted to address this significant health problem, the exact mechanism by which CS induces ED is not fully understood. The ultimate goal of this thesis; therefore, is to study the mechanisms by which CS induces ED, aiming at the development of new therapeutic strategies that can be used in protection and/or reversal of CS-induced ED. In the first part of this study, we developed a well-characterized animal model for chronic secondhand smoke exposure (SHSE) to study the onset and severity of the disease. In this model, SHSE impaired endothelium-dependent relaxation and triggered persistent hypertension in a time-dependent manner. This impairment was accompanied by over-production of superoxide (O2.-) through activation of NADPH oxidase and endothelial nitric oxide synthase (eNOS) uncoupling. Moreover, SHSE led to a decrease in eNOS expression and phosphorylation. In the second part of this study we used a cell model for CS-exposure to investigate the mechanism of CS-induced eNOS uncoupling. Exposure of bovine aortic endothelial cells (BAECs) to cigarette smoke extract (CSE) resulted in a significant decrease in nitric oxide (NO) production with concomitant increase in O2.- generation as a result of BH4 depletion and eNOS uncoupling. Moreover, CSE exposure led to a decrease in GTPCH and eNOS protein expression and eNOS phosphorylation level at ser 1179. More importantly, exposure of BAECs to CSE increased the level of ubiquitinylated protein and increased 26S proteasomal activity. Inhibition of the 26S proteasome partially prevented CSE-induced reduction of Tetrahydrobiopterin (BH4), total biopterin, Guanisin tri phosphate cyclohydrolase 1 (GTPCH) level, eNOS level, and increased NO production following CSE exposure, indicating a central role of the proteasome in CSE-induced eNOS dysfunction. Finally, we examined the existence and role of eNOS S-glutathionylation in CS-induced ED. Exposure of BAECs to CSE led to an increase in O2.- generation and depletion of cellular reduced glutathione. More importantly, S- glutathionylation of total cellular proteins and eNOS was significantly higher in CSE-exposed cells and tissue homogenates obtained from rat aortas that were exposed to CSE. Incubation with Dithiothreitol (DTT) enhanced eNOS function and decreased eNOS S-glutathionylation in rat aorta, and decreased O2.- generation through reversal of eNOS S-glutathionylation in CSE-exposed cells. In conclusion, the results from this thesis work provide an important insight toward better understanding of the pathogenesis of CS-induced ED. Furthermore, we explored a new mechanism that should be targeted as a therapeutic option for treatment and prevention of CS-induced ED.
Jay Zweier (Advisor)
Amal Amer (Committee Member)
Arthur Strauch (Committee Member)
198 p.

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Citations

  • Abdelghany, T. M. I. (2013). Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1367438410

    APA Style (7th edition)

  • Abdelghany, Tamer. Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1367438410.

    MLA Style (8th edition)

  • Abdelghany, Tamer. "Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1367438410

    Chicago Manual of Style (17th edition)