Excitation-contraction (EC) coupling and calcium (Ca2+) cycling play an important role in regulating cardiac contractile force and in the development of cardiac diseases. Disturbance of Ca2+ handling occurs at multiple levels in heart failure and is closely related to pathological performance. However, there are limited means to evaluate alterations in EC coupling in vivo. Recent studies have indicated the role of neuronal NOS (nNOS) in regulating EC coupling, with several aspects of nNOS modulation of myocardial contractility and its role in cardiac diseases still poorly understood. In the heart, nNOS has been reported to be associated with the sarcolemma, sarcoplasmic reticulum (SR), and mitochondria. Co-localization of nNOS with its effector proteins has been suggested to be important mechanisms in myocardial control. However, studies that employ a global nNOS knockout model, the NOS1-/- mouse, cannot address the complexities of NO action through spatial confinement. Therefore, the objectives of the proposed research are 1) to develop manganese-enhanced magnetic resonance imaging (MEMRI) methods for in vivo characterization of Ca2+ uptake in myocardium, the first-step in Ca2+ cycling;2) to apply state-of-the-art MRI technology to the investigation of the differential roles of nNOS in the regulation of cardiac function and the development of cardiomyopathy. We will characterize two mouse models that differ in nNOS disruption, i.e., the global nNOS knockout mouse and the 1-dystrobrevin knockout mouse, which leads to the disruption of nNOS in cell membrane only. By combining in vivo MRI characterization of cardiac phenotypes such as function and Ca2+ uptake with in vitro molecular/cellular analysis of myocyte contractility and Ca2+ cycling in a systematic comparative study of novel mouse models with distinctive modes of nNOS disruption, this approach offers unique opportunity for dissecting the roles of nNOS in regulating cardiac function in distinct subcellular compartments. The mechanistic elucidation of the effects of nNOS on myocardial contraction and disease progression will allow nNOS to be a therapeutic target in cardiovascular diseases.

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Excitation-contraction (EC) coupling and calcium cycling play an important role in regulating cardiac contractile force and in the development of cardiac diseases. Neuronal nitric oxide synthase (nNOS) regulates several key processes in EC coupling and is abnormal in heart failure. Pharmacological intervention that targets nNOS may be effective treatment for heart failure. The goal of the proposed research is to develop in vivo imaging method that is sensitive to altered calcium cycling, and to apply this method to elucidate the role of nNOS in EC coupling and cardiac function in mouse models of nNOS disruption.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Evans, Frank
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Case Western Reserve University
Biomedical Engineering
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United States
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Jiang, Kai; Li, Wen; Li, Wei et al. (2015) Rapid multislice T1 mapping of mouse myocardium: Application to quantification of manganese uptake in ?-Dystrobrevin knockout mice. Magn Reson Med 74:1370-9
Montano, Monica M; Desjardins, Candida L; Doughman, Yong Qui et al. (2013) Inducible re-expression of HEXIM1 causes physiological cardiac hypertrophy in the adult mouse. Cardiovasc Res 99:74-82
Desjardins, Candida L; Chen, Yong; Coulton, Arthur T et al. (2012) Cardiac myosin binding protein C insufficiency leads to early onset of mechanical dysfunction. Circ Cardiovasc Imaging 5:127-36
Lu, Ming; Atthe, Bharath; Mateescu, Gheorghe D et al. (2012) Assessing mitochondrial respiration in isolated hearts using (17)O MRS. NMR Biomed 25:883-9
Lu, Ming; Banerjee, Suhanti; Saidel, Gerald M et al. (2011) Regulation of cytosolic and mitochondrial oxidation via malate-aspartate shuttle: an observation using dynamic ¹³C NMR spectroscopy. Adv Exp Med Biol 701:185-92
Li, Wei; Bian, Fang; Chaudhuri, Priyanjana et al. (2011) Delineation of substrate selection and anaplerosis in tricarboxylic acid cycle of the heart by 13C NMR spectroscopy and mass spectrometry. NMR Biomed 24:176-87
Zhong, Jia; Yu, Xin (2010) Strain and torsion quantification in mouse hearts under dobutamine stimulation using 2D multiphase MR DENSE. Magn Reson Med 64:1315-22
Li, Wei; Yu, Xin (2010) Quantification of myocardial strain at early systole in mouse heart: restoration of undeformed tagging grid with single-point HARP. J Magn Reson Imaging 32:608-14
Chen, Yong; Somji, Aleefia; Yu, Xin et al. (2010) Altered in vivo left ventricular torsion and principal strains in hypothyroid rats. Am J Physiol Heart Circ Physiol 299:H1577-87
Li, Wen; Griswold, Mark; Yu, Xin (2010) Rapid T1 mapping of mouse myocardium with saturation recovery Look-Locker method. Magn Reson Med 64:1296-303

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