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ION CHANNELS, PROTEIN KINASE C AND CAVEOLAE IN CARDIOPROTECTION

Kang, Chen
http://rave.ohiolink.edu/etdc/view?acc_num=osu1449158171

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Ischemic heart disease is one of the leading causes for death in the whole world. It has been the top one killer. In general, ischemic heart disease results from the blockage of the arteries so the blockage in the arteries reduces the supply of blood to the heart muscle causing severe consequences such as heart attack. Treatment for ischemic heart disease involves improving blood flow to the heart muscle. Treatment may include medications, a procedure to open blocked arteries or bypass surgery. Until now, scientists are still looking for more effective ways to reduce the damage to the heart from ischemic heart disease. Cardiac cells preserve a variety of mechanisms in order to protect them from myocardial ischemia. In 1986, Murry and colleagues found out that repeated short episodes of sub-lethal ischemia protected the myocardium against a subsequent lethal ischemic insult which is defined as ischemic preconditioning (IPC). IPC is a powerful form of endogenous protection against myocardial infarction, which has been demonstrated in several animal species and, recently, in isolated human cardiomyocytes. In addition to IPC and its powerful role in cardioprotection, there are numerous other signalings and effectors contributing to the cardioprotection against ischemia. One of them is TASK1 channel, which stabilizes resting membrane potential especially during cardiac ischemia/hypoxia because disruption of ion homestasis eventually causes cell death. Activation of protein kinase C (PKC) via adenosine receptors is known to be involved in the cardioprotection of ischemic preconditioning. Speci¿cally, activated PKCe translocates to mitochondria is thought to be critical of cardioprotection. However, it is still elusive how PKCe translocates to mitochondria. The present study was designed to determine how activation of adenosine receptor induces translocation of PKCe to mitochondria and whether this translocation is age-dependent (Chapter 2). In addition, the two-pore domain potassium channel TASK1 is strongly expressed in the heart and has been shown to regulate the resting membrane potential and action potential. Modulation of the TASK1 background currents provides a mechanism for control of cellular excitability. However, little is known about the localization and regulation of TASK1 in the heart especially whether TASK1 is modulated by caveolar microdomain -- one of the most abundant microstructure in cardiac cells. So the following study was designed to determine whether TASK1 is modulated by caveolin-3 (Cav-3) via association with Cav-3 (Chapter 3). We were further interest in whether TASK1 channels play protective role in myocardial hypoxia. We were trying to investigate the molecular mechanisms by which hypoxia regulates TASK1 channels (Chapter 4). In conclusion, we demonstrate that adenosine-induced translocation of PKCe to mitochondria is mediated by caveolin-3-dependent PKC signaling and this process is age-related, possibly through regulation of HSP90 and TOM70 expression. Moreover, our study indicates that TASK1 is functionally regulated by Cav-3 probably mainly through association with Cav-3. In the following study, we found out that TASK1-like channels plays a protective role in cardiac hypoxia. TASK1-like channels were blocked by hypoxia mimicked by metabolic inhibition and this inhibition was mainly through the activation of PKC. These results not only point out a novel mechanism in regulating PKC function in mitochondria which is involved in ischemic preconditioning against ischemia but also illustrate regulation of cardiac TASK1 channels and protective role in cardiac hypoxia. Above all, our data are supportive for possible roles of mitochondrial translocation of PKCe and TASK1 channels in the cardioprotection against hypoxia. Thus, the work presented in this thesis is not only important for a better understanding of signaling related to preconditioning and modulation of TASK1 in cardiomyocytes, but also provides with potential effectors in cardioprotection against ischemia in the future studies.
Keli Hu (Advisor)
Lane Wallace (Committee Member)
Nam Lee (Committee Member)
181 p.
Pharmacology

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Citations

  • Kang, C. (2015). ION CHANNELS, PROTEIN KINASE C AND CAVEOLAE IN CARDIOPROTECTION [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449158171

    APA Style (7th edition)

  • Kang, Chen. ION CHANNELS, PROTEIN KINASE C AND CAVEOLAE IN CARDIOPROTECTION. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1449158171.

    MLA Style (8th edition)

  • Kang, Chen. "ION CHANNELS, PROTEIN KINASE C AND CAVEOLAE IN CARDIOPROTECTION." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449158171

    Chicago Manual of Style (17th edition)

osu1449158171
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