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THE ROLE OF ENGINEERED CARDIAC TROPONIN C L48Q IN HEALTH AND DISEASE

Shettigar, Vikram
http://rave.ohiolink.edu/etdc/view?acc_num=osu1461158879

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Heart failure has become the biggest cause of death worldwide. It is now understood to be a physiologically and molecularly complex phenomenon resulting from a variety of etiologies ranging from genetic factors, age, unhealthy lifestyles and other comorbidities. Over the past half century, a variety of attempts have been made by clinicians and researchers to “cure”, or at minimum retard the progression of heart failure. In the process, a series of hypotheses were proposed for the root cause of the failing heart. A variety of pharmacological agents have been developed based on these hypotheses, which have unfortunately only made moderate improvements in long term cardiac function and ultimately patient survival. There are currently no approaches that have been able to reverse or even halt the progression of heart failure. One of the major problems observed during cardiac dysfunction is aberrant contractility and impaired force generation. All the proposed hypothesis of heart failure either directly or indirectly translates to reduced force generation. Thus, pharmacologically targeting the components of the myofilament to augment force generation has been a strong therapeutic rationale. However, these pharmacological agents (Ca2+ sensitizing compounds), have led to limited clinical success but with severe side effects, thus necessitating development of novel strategies. Cardiac Troponin C (TnC), integrates information from the myofilament and regulates cardiac contraction in response to the Ca2+ signal. With the advent of protein engineering and molecular approaches, genetically adjusting Ca2+ sensitivity of TnC has been accomplished. Delivering these TnC variants by gene therapy based strategies in vivo into pre-clinical murine models allows us to test their role in normal and disease conditions. Delivery of desensitized TnC (D73N) showed a dilated cardiomyopathy like phenotype while sensitized TnC (L48Q TnC) showed improved myocyte contractility with no in vivo adverse effects. The studies present here within are a comprehensive determination of the role of Ca2+ sensitized L48Q TnC in health and cardiovascular diseases. The cardiac structure and function of L48Q TnC mice were not different form uninjected control wild type or wild type TnC mice. Neither did they show any arrhythmias under basal or beta-adrenergic stimulation. However, under hemodynamic measurements, L48Q TnC mice showed significantly higher levels of contractility without affecting the cardiac reserve or relaxation. Enhanced cardiac contractility of L48Q TnC mice clearly indicated the ability of the heart to perform better under increased demand or stress. To attest to this, when the mice we subjected to strenuous physical activity on a treadmill, they showed better exercise tolerance which is a clinically reliable parameter for cardiac performance. These characteristics are ideal for a positive inotrope to be used for augmenting contractility to combat depressed cardiac function or increased demand. L48Q TnC protected cardiac function from a myocardial infarction even though there was no salvage or generation of ventricular tissue. L48Q TnC mice also showed better exercise tolerance indicating preserved cardiac performance. Similarly under the setting where L48Q TnC was expressed after myocardial infarction, a more therapeutic situation, mice showed improved cardiac function and performance leading to improved survival. Thus, the positive inotropic effects of L48Q TnC were able to protect and improve cardiac function in a murine model of myocardial infarction. Similarly, in murine models of increased cardiac demand as seen in trans-aortic constriction and Angiotensin II infusion, the L48Q TnC mice resisted the drop in cardiac function and adverse remodeling. An exciting observation was that the L48Q TnC expressing mice resisted the age associated reduction in ejection fraction and lived substantially longer. Although these studies are incomplete, it would appear that TnC L48Q has a broad applicability to aiding a spectrum of cardiovascular diseases. In summary, these results have provided much insight on the potential of deriving novel therapeutic strategies through precise engineering and gene therapy of TnC. This opens the door for a plethora of possibilities and therapeutic directions to target heart failure and cardiomyopathies.
Jonathan Davis (Advisor)
173 p.
Molecular Biology; Physiology

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Citations

  • Shettigar, V. (2016). THE ROLE OF ENGINEERED CARDIAC TROPONIN C L48Q IN HEALTH AND DISEASE [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461158879

    APA Style (7th edition)

  • Shettigar, Vikram. THE ROLE OF ENGINEERED CARDIAC TROPONIN C L48Q IN HEALTH AND DISEASE. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1461158879.

    MLA Style (8th edition)

  • Shettigar, Vikram. "THE ROLE OF ENGINEERED CARDIAC TROPONIN C L48Q IN HEALTH AND DISEASE." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461158879

    Chicago Manual of Style (17th edition)

osu1461158879
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