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Relengthening RT50, Fig 3C-G) Neuronal Nitric Oxide Synthase Signaling Contributes to the Beneficial Cardiac Effects of Exercise DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Steve R. Roof Biomedical Sciences Graduate Program The Ohio State University 2012 Dissertation Committee: Dr. Mark T. Ziolo, PhD Advisor Dr. George E. Billman, PhD Dr. Sandor Gyorke, PhD Dr. Brandon Biesidecki, PhD ABSTRACT Exercise is beneficial to one’s health, reduces the risk of cardiomyopathies, and is utilized as a therapeutic intervention after disease [2-7]. This is due, in part, due to the beneficial chronic adaptations that enhance contraction and accelerate relaxation [8]. These intrinsic exercise-induced adaptations are observed at the level of the cardiomyocyte [9]. That is, ventricular myocytes from exercised (Ex) mice exhibit increased Ca2+ cycling and contraction-relaxation rates [6, 9-12]. Additionally, cardiac growth (physiological hypertrophy) and an increase in aerobic fitness (VO2max) are hallmark cardiac adaptations due to exercise training. The molecular mechanisms that explain how the heart adapts are not fully understood and studies examining signaling pathways are limited. A signaling molecule with a potential role in cardiac adaptations to exercise is nitric oxide (NO). Nitric Oxide (NO) has been shown to be a key regulator of myocyte contractile function. NO, produced via the neuronal nitric oxide synthase (nNOS or NOS1), enhances basal contraction by increasing Ca2+ cycling through the sarcoplasmic reticulum (SR) [13-15]. Data suggest that NOS1 signaling increases Ca2+ uptake by targeting the SR Ca2+ ATPase (SERCA2a)/phospholamban (PLB) complex. NOS1 signaling also targets the SR Ca2+ release channel (ryanodine receptor - RYR2) to increase its open time probability [16]. Together, NOS1 signaling increases Ca2+ transient amplitudes, shortening amplitudes, and accelerates relaxation rates [14, 16-19]. These are similar ii effects to exercise adaptations, but the role of NOS1 signaling on the beneficial effects of exercise on cardiac myocyte function has not been thoroughly investigated. Thus, we have set up 5 specific goals. We want to 1) determine if exercise enhances NOS1 protein expression and NOS1-dependent NO bioavailability in murine ventricular myocytes, 2) determine if NOS1 contributes to the exercise-mediated enhancement of murine myocyte contraction, 3) determine the molecular mechanisms of the NOS1-mediated increase in murine contraction, 4) investigate the exercise-mediated cardiac adaptations (VO2max, physiological hypertrophy, and myocyte contraction) in the NOS1 knockout (NOS1KO) mouse, and 5) determine if NOS1 signaling contributes to the exercise-mediated enhancement of contraction in a large mammal model. The results are as follows: After an 8 week aerobic interval training program, Ex mice had a higher VO2max and a physiological hypertrophy compared to sedentary (Sed) wildtype (WT) mice. Exercise induced an increase in NOS1 expression and nitric oxide production. Isolated ventricular myocytes from the Ex mice exhibited larger contraction and faster relaxation rates compared to Sed myocytes. Acute NOS1 inhibition with S-methyl-L-thiocitrulline 2+ 2+ (SMLT) resulted in a greater reduction in Ca transient amplitude, Ca transient RT50, shortening amplitude, SR Ca2+ load, and SR Ca2+ fractional release in Ex versus Sed. In fact, acute NOS1 inhibition normalized the Ex induced increase in contraction and Ca2+ decline rates to Sed levels. The NOS1 mediated effect on contraction was due to a shift in the kinase/phosphatase balance to increase PLB Serine16 phosphorylation (the PKA site). Surprisingly, trained NOS1KO mice, did not exhibit any of the cardiac adaptations. That iii is, Ex-NOS1KO mice did not have increased VO2max or hypertrophy compared to Sed- NOS1KO mice. In fact, Ex-NOS1KO mice had depressed Ca2+ transient amplitude, SR 2+ 2+ Ca load, and slowed Ca transient RT50 compared to Sed-NOS1KO. Upon further investigation, this resulted from elevated reactive oxygen species levels that contributed to increase protein phosphatase activity and subsequently decrease PLB Serine16 phosphorylation to cause detrimental Ca2+ handling. Lastly, we observed a similar effect in an exercise-trained canine model. Specifically, NOS1 inhibition elicited a greater reduction in myocyte contraction in Ex versus Sed. These data strongly suggest a more universal role for exercise induced enhancement of NOS1 signaling in both large and small mammalian species In conclusion, NOS1 signaling contributes to the adaptive cardiac effects of exercise. Specifically, exercise increases ventricular myocyte NOS1 expression and NO bioavailability, which is essential for aerobic fitness, hypertrophy, and enhanced contraction/relaxation. Hence, it may be possible to mimic the beneficial effects of exercise to the heart by enhancing NOS1 signaling. This pathway may provide a novel therapeutic for cardiac patients that are unable/unwilling to exercise. iv DEDICATED TO THE WOMEN IN MY LIFE – PAM, AMANDA, & SIENA ROOF v ACKNOWLEDGMENTS I remember where I was when the thought of combining my passion for exercise and medicine into a thesis project materialized. That is when ELIM (Exercise-Like Induced Medicine) was born. From that point on, I’ve dedicated my time investigating how a normal heart is strengthened into an exercise-trained heart. With luck on my side, I met up with Dr. Mark Ziolo, and together, we found evidence that strongly suggest the NOS1 is indeed necessary for the heart to adapt to exercise. This achievement did not come easy and there are plenty of people who deserve thanks. I first want to thank my dissertation committee for their help and guidance on my project: Drs. George Billman, Sandor Gyorke, and Brandon Biesidecki. Next I would like to thank other laboratories and their members (graduate students and lab techs alike) in the department and college for the collaborations and insight into science: Drs. Jonathan Davis, Paul Janssen, Peter Mohler and others. It goes without question that a large amount of my thanks goes to my wife, Amanda, for putting up with my long hours. Her sacrifices truly provided me with enough time to accelerate and complete my project. Lastly, I have to thank the single most important person who deserves to be acknowledged for his efforts in helping me complete my Ph.D., and that is my advisor Dr. Mark Ziolo. With very little lab experience prior to graduate school, Dr. Ziolo brought me in and allowed me to chase after my dream of seeing if ELIM could become vi a reality. He dealt with my naive science immaturity and horrible speaking/writing skills in a very mentoring-like fashion. He kept me motivated and provided with nearly every tool needed. Without his outside of the lab friendship, my time spent in his lab would not have been as enjoyable. If it wasn’t for Dr. Ziolo, I would not have had such a successful Ph.D. vii VITA July 22nd, 1984. Born, Canton, OH 2003-2008. .B.S. Biochemistry and Exercise Science, Florida State University 2008-2012. Graduate Research Associate, Department of Physiology and Cell Biology, The Ohio State University PUBLICATIONS 1. Kohr MJ, Traynham CJ, Roof SR, et al. cAMP-independent activation of protein kinase A by the peroxynitrite generator SIN-1 elicits positive inotropic effects in cardiomyocytes. J Mol Cell Cardiol. 2010;48(4):645-8. 2. Roof SR, Janssen PM, Ziolo MT, The Effects of Increased Systolic Ca2+ and/or Phospholamban Serine16 Phosphorylation on Ca2+ Transient Kinetics in Cardiac Myocytes, Am J Physiol Heart Circ Physiol 2011; 301(4):H1570-8. 3. Roof SR, Biesiadecki BJ, Davis JP, Janssen PM, Ziolo MT, Effects of increased systolic Ca2+ and β-adrenergic stimulation on Ca2+ transient decline in NOS1 knockout cardiac myocytes, Nitric Oxide, 2012 1;27(4):242-7. 4. Roof SR, Tang L, Ostler JE, Periasamy M, Györke S, Billman GE, Ziolo MT, Neuronal Nitric Oxide Synthase is Indispensable for the Adaptative Contractile Effects of Exercise, SUBMITTED 5. Traynham CJ, Roof SR, Wang H, Prosak RA, Tang L, Viatchenko-Karpinski S, Ho HT, Racoma IO, Catalano DJ, Huang X, Han Y, Kim SU, Gyorke S, Billman GE, Villamena FA, Ziolo MT, Di-esterified nitrone restores nitroso-redox balance and increases myocyte contraction via increased SR Ca2+ handling, IN PRESS, PLOS One. 6. Curran J, Tang L, Roof SR, Velmurugan S, Millard A, Shonts S, Santiago DJ, Ahmad A, Perryman M, Mohler P, Bers DM, Ziolo MT, Shannon TR, Nitric viii Oxide Mediates Increased Diastolic Sarcoplasmic Reticulum Calcium Release in Response to Adrenergic Agents, SUBMITTED 7. Kohr MJ, Roof SR, Zweier JL, Ziolo MT, Modulation of Myocardial Contraction by Peroxynitrite, SUBMITTED 8. Jeyaraj SC, Roof SR, Unger NT, Mohler P, Ziolo MT, Chotani MA, Effects of Rap1a GTPase on cardiac myocyte function, IN PREPARATION 9. Roof SR, Ho T, Tang L, Haung X, Catalano DJ, Györke S, Ziolo MT, Elevated Reactive Oxygen Species Elicits the Detrimental Effects of Exercise in the Neuronal Nitric Oxide Synthase Knockout Mice, IN PREPARATION 10. Oaks JJ, Santhanam R, Walker CJ, Saddoughi S, Roof SR, Chen C-S, Ziolo MT, Levine R, Quintas-Cardama A, Ogretmen B, Perrotti D. The oncogenic Jak2V617F mutant and the phosphorylated form of the sphingosine analog FTY720 (FTY720-P) inhibit the tumor suppressor protein phosphatase 2A (PP2A) through a Jak2, SET and Nitric Oxide-dependent signaling pathway, IN PREPARATION 11. Peterson JM, Roof SR, Canan BD, Little SC,
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