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Regulation of Cardiac Calcium Signaling in Disease

Baine, Stephen Hardy
http://orcid.org/0000-0002-1671-4652
http://rave.ohiolink.edu/etdc/view?acc_num=osu1577952665232614

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Heart Failure (HF) contributes significantly to morbidity and mortality in the United States.(1) Current treatment regimens rely on pharmacological blockade of the β-adrenergic system and angiotensin converting enzyme inhibitors to prevent adverse functional and structural remodeling in the heart. These therapies have proved valuable in improving survival in HF and are a mainstay of current treatment guidelines.(2) Unfortunately, approximately half of HF patients die within the first five years of original diagnosis.(3) Thus, novel therapies are warranted to reduce the current and future burden of HF. Over the last decade significant effort has been devoted to identifying and delineating the relationship between the sympathetic nervous system and cardiovascular disease. However, much less is known about parasympathetic modulation of heart function in both physiological and pathophysiological settings. At the same time, it has been shown that HF is characterized by sympathetic over-activation with a concomitant parasympathetic withdrawal.(4) Thus, treatments to augment or increase parasympathetic output have recently emerged and were shown to improve ventricular function in HF in both animals and humans.(5) However, the mechanisms involved in regulating the beneficial effects of these therapies are currently unknown. This work examines the molecular signaling mechanism/s of cholinergic stimulation and regulation of cardiac myocytes. We define a novel signaling pathway which links functional changes in phosphorylation of the critical calcium release channel, the ryanodine receptor (RyR2), to PI3K-AKT-NO signaling in cardiomyocytes. Previously unrecognized in adult ventricular cardiomyocytes, our work provides insights into compartment specific signaling in ventricular myocytes. Amplification or modulation of this pathway could provide an avenue for potential therapies to improve contractility in HF. Furthermore, this work assesses the therapeutic efficacy of an FDA approved acetylcholinesterase inhibitor, Pyridostigmine, in a pre-clinical model of HF. Here we report Pyridostigmine improves ventricular function and reduces abnormal calcium dysregulation in HF mice. Additionally, we report a mechanistic link between calcium dysregulation (leak) via reduction in abnormal RyR2 phosphorylation. Taken together our findings suggest Pyridostigmine as a potential therapy for HF and should be explored further in human clinical trials. In summary, our data present several opportunities for potential therapies in HF. In one sense, taking advantage of our purported signaling pathway in Chapter 2, designing therapies exploiting/ or amplifying certain signaling partners could be considered as an avenue to improve calcium cycling in disease. At the same time, Pyridostigmine, an FDA established clinically tolerated compound, improved cardiac function and reduced calcium dysregulation at the cellular level. Although these pathways have shown some therapeutic efficacy in mice, studies with larger animal models would need to be conducted to validate our findings. Since HF is a complex disorder and disease etiology varies significantly, it is important to state that many signaling pathways contribute to HF. Thus, altering or preventing signaling at a single node may not be sufficient to overcome disease, but would need to be consider in the context of other proven therapies.
Cynthia Carnes, PharmD, PhD (Advisor)
Sandor Gyorke, PhD (Committee Member)
Przemyslaw Radwanski, PharmD, PhD (Committee Member)
120 p.
Pharmacology; Pharmacy Sciences

Recommended Citations

Citations

  • Baine, S. H. (2020). Regulation of Cardiac Calcium Signaling in Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1577952665232614

    APA Style (7th edition)

  • Baine, Stephen. Regulation of Cardiac Calcium Signaling in Disease. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1577952665232614.

    MLA Style (8th edition)

  • Baine, Stephen. "Regulation of Cardiac Calcium Signaling in Disease." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1577952665232614

    Chicago Manual of Style (17th edition)

osu1577952665232614
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© 2020, some rights reserved.Creative Commons License Regulation of Cardiac Calcium Signaling in Disease by Stephen Hardy Baine is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.