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Effects of Neuronal Nitric Oxide Synthase Signaling on Myocyte

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Effects of Neuronal Nitric Oxide Synthase Signaling on Myocyte Effects of Neuronal Nitric Oxide Synthase Signaling on Myocyte Contraction during β- Adrenergic Stimulation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Lifei Tang Biophysics Graduate Program The Ohio State University 2013 Dissertation Committee: Dr. Mark T. Ziolo, PhD Advisor Dr. Brandon Biesiedecki, PhD Dr. Jonathan Davis, PhD Dr. Sandor Gyorke, PhD a Copyright by Lifei Tang 2013 i ABSTRACT Nitric oxide (NO) is known to be a key regulator of cardiac contraction. Within ventricular myocytes, NO is produced by two constitutively expressed NO synthase (NOS) isozymes, NOS1 and NOS3. It is well defined that NOS1 signaling results in positive inotropic and lusitropic effects under baseline conditions. This effect is largely due to the phosphorylation of phospholamban (PLB) at Ser16 by the cAMP-dependent protein kinase (PKA) up-regulating sarcoplasmic reticulum (SR) Ca2+ uptake. In addition, our lab also demonstrated that NOS1 increases ryanodine receptor (RyR) activity via S-nitrosylation up- regulating SR Ca2+ release. Physiologically, heart function is largely regulated by the β-adrenergic (β-AR) pathway leading to positive inotropy and lusitropy. Alterations in the β-AR pathway contribute to the contractile dysfunction, adverse remodeling, and arrhythmias in many cardiac diseases (i.e. heart failure (HF)). The purpose of this dissertation is to investigate the role of NOS1 signaling during β-AR stimulation. Previous studies have shown that NOS1 signaling contributes to the positive inotropy, but not lusitropy, during β-AR stimulation. Interestingly, unlike under baseline conditions, PLB phosphorylation is not altered in the condition of NOS1 deficiency (acute NOS1 inhibition or NOS1 knockout) during β-AR stimulation. Thus, it is clear that there are other end targets of NOS1 other than ii PLB during stimulation of the β-AR pathway, possibly RyR. Hence the molecular mechanisms of NOS1 signaling during -AR stimulation are not known. Phosphorylation of RyR by the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) has been reported to be the main cause of the enhanced SR Ca2+ release during β-AR stimulation. CaMKII is activated in response to β-AR stimulation and also has positive inotropic effects. Unfortunately, increased CaMKII activity, which occurs in many heart diseases (i.e. hypertrophy and HF), leads to Ca2+ mishandling. Given that RyR is reported to be co-localized with NOS1 and CaMKII, we are interested in whether the CaMKII pathway crosstalks with the NOS1 pathway to regulate RyR activity during β-AR stimulation. In addition, the upstream activator of NOS1 during β-AR stimulation is not known. There is an Akt dependent phosphorylation site (Ser1416) on NOS1 which is reported to stimulate NOS1 activity, and it is known that Akt activity is increased during β-AR stimulation. Therefore, we will also investigate the possible activation of NOS1 by Akt during -AR stimulation. We first investigated if NOS1 signaling was necessary for the enhanced SR Ca2+ leak during β-AR stimulation. Rabbit ventricular myocytes displayed decreased -AR stimulated (isoproterenol, ISO) SR Ca2+ leak in the presence of acute, non-specific NOS inhibition by L-NG-Nitroarginine methyl ester (L-NAME). Additional experiments indicated that NOS1 but not NOS3 was the NOS isozyme involved. Specifically, β-AR stimulated SR Ca2+ leak was only decreased by NOS1 inhibition (S-Methyl-L-thiocitrulline (SMLT)), but not NOS3 inhibition (L-N5- (1-Iminoethyl) ornithine (L-NIO)). We next determined if the NOS1 mediated iii increase in SR Ca2+ leak during β-AR stimulation is via CaMKII. In isolated wildtype (WT) mouse myocytes, β-AR stimulated SR Ca2+ leak was decreased withCaMKII inhibition by KN93. However, KN93 had no effect on the already blunted -AR stimulated SR Ca2+ leak in NOS1 knockout myocytes (NOS1-/-). Simply resupplying NO with S-Nitroso-N-acetyl-DL-penicillamine (SNAP) increased SR Ca2+ leak; and this effect was blocked by CaMKII inhibition, suggesting that CaMKII is downstream of NOS1. We then determined if the NOS1/CaMKII-mediated increase in SR Ca2+ leak during β-AR stimulation also involves RyR modulation. RyR Ser2814 phosphorylation (CaMKII site) was increased in WT hearts during β-AR stimulation and was significantly blunted in NOS1-/- hearts. We performed further experiments using RyR knockin mice (CaMKII phosphorylation constitutively active (S2814D) or ablated (S2814A)) to determine if RyR is the end target of NOS1/CaMKII signaling. During -AR stimulation, NOS1 inhibition decreased SR Ca2+leak in WT myocytes but showed no effect in the RyR knockin myocytes. These data suggest that RyR is the end target of NOS1/CaMKII signaling. We then investigated if the NOS1/CaMKII/RyR axis contributes to the positive inotropic effect of β-AR stimulation. In WT myocytes, CaMKII inhibition decreased -AR stimulated myocyte contraction (simultaneous measurement of Ca2+ transients with Fluo-4 and cell shortening by edge detection). In NOS1-/- myocytes, CaMKII inhibition had no effect on the already blunted -AR stimulated contraction. Interestingly, resupply of NO via SNAP increased -AR stimulated contraction in NOS1-/- myocytes, and this effect was completely blocked by iv CaMKII inhibition. Consistent with these data, -AR stimulated fractional release (an indicator of RyR activity) was decreased with CaMKII inhibiton in WT myocytes but not in NOS1-/- myocytes. We investigated the molecular mechanisms of the NOS1-mediated CaMKII activation. Western blot revealed that CaMKII autophosphorylation (Thr287) was increased in WT but not altered in NOS1-/-myocytes during -AR stimulation. This effect was associated with an increase in CaMKII S-nitrosylation levels (western blot). Further, we found that NO (SNAP) can directly activate CaMKII in vitro (CaMKII activity kit). These data indicate that NOS1 signaling directly increases CaMKII activity via S-nitrosylation to increase autophosphorylation levels. We performed additional experiments and excluded other potential mediators of CaMKII activation (Epac and oxidation) and RyR activity (PKA phosphorylation). We designed experiments to determine if NOS1 signaling is activated by Akt during β-AR stimulation. Our data demonstrate that both SR Ca2+ leak and NOS1 phosphorylation at Ser1416 (Akt site) were decreased by Akt inhibition (Akt inhibitor X) in isolated rabbit myocytes. Further, Akt inhibition (Akt inhibitor V) decrease β-AR-stimulated myocyte contraction in WT myocytes but had no effect in NOS1-/- myocytes. Lastly, we determined if NO-dependent increase in RyR activity is involved in arrhythmogenesis during β-AR stimulation. NOS inhibition (L-NAME) attenuated ISO-stimulated spontaneous Ca2+ waves (SCaW) in rabbit myocytes and Ca2+aftertransients in failing human trabeculae.These data suggest that v NOS-mediated CaMKII activitation in the pathological heart may be of significance. In conclusion, these data suggest that during β-AR stimulation, NOS1 is activated by Akt and contributes to the positive inotropy via CaMKII-mediated RyR activation. This pathway may also be involved in the arrhythmogenesis of the heart. vi DEDICATED TO MY FAMILY – SHANJIN TANG, GUIXIU LI, AND HAIYING XING. vii ACKNOWLEDGEMENT Foremost, I would like to express my deepest appreciation to my advisor, Dr. Mark Ziolo, for his continuous support of my Ph.D study. He was always patient in teaching me experimental design, experimental techniques, data analysis, and helped me improve my writing/speaking skills. He can promptly unravel the positive information from my research results and point out the right direction with his immense knowledge and sharp observation. His motivation and enthusiasm on science encourage me to bravely face the frustration and distress in research. He is generous and always fully supportive of my applications to grants and conferences. In the past five years, his continuous guidance helped me in my research and writing of this thesis. Dr. Ziolo is not only a good advisor, but also a good friend. He has a great sense of humor, and curiosity to foreign cultures. His lab has a very comforting environment. I could not have imagined having a better advisor and mentor for my time as a Ph.D. student. Besides my advisor, I would like to thank the rest of my thesis committee: Dr. Sandor Gyorke, Dr. Jonathan Davis, and Dr. Brandon Biesiadecki, for their encouragement, fair and sharp questions, insightful suggestions, and collaboration. This thesis was born from a discussion between Drs. Tom Shannon, Jerry Curran and Mark Ziolo. Thus, I would like to thank Drs. Shannon (and his group) viii and Curran for their indispensable and key contributions to this thesis. Further, I would like to thank the support and help given by the other collaborators and their group members: Drs. Peter Mohler, Thomas Hund and Paul Janssen. Next I want to thank my current and previous labmates: Dr. Honglan Wang, Dr. Bo Zhang, Dr. Steve Roof, Xin Huang, and Dr. Christopher Traynham for their help and guidance during my time in the lab. Last but not least, I would like to thank my family: my parents Shanjin Tang and Guixiu Li for giving birth to me and trusting me throughout my life; my husband Haiying Xing, the magic man I met in the US, for waiting and supporting me for the past 4 years. ix VITA April 6th, 1984. Born, Hunan, China 2001-2005. B.S. Biotechnology, Wuhan University, China 2005-2008. .M.S. Biochemistry and Molecular Biology, Wuhan University, China 2008-2013. .Graduate Research Associate, Department of Physiology and Cell Biology, The Ohio State University PUBLICATIONS 1. Tang L, Wang H, Ziolo MT. Targeting NOS as a Therapeutic Approach in Heart Failure. Pharmacology & Therapeutics. ACCEPTED 2. Curran J*, Tang L*, Roof SR, Velmurugan S, Millard A, Shonts S, Wang H, Ahmad DSU, Perryman M, Bers DM, Mohler PJ, Ziolo MT*, Shannon TR*. Nitric Oxide-dependent Activation of CaMKII Increases Diastolic Sarcoplasmic Reticulum Calcium Release in Cardiac Myocytes in Response to Adrenergic Stimulation. PLOS ONE. SUBMITTED *Authors contributed equally 3.
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