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.
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.
|Jiang, Kai; Jiao, Sen; Vitko, Megan et al. (2016) The impact of Cystic Fibrosis Transmembrane Regulator Disruption on cardiac function and stress response. J Cyst Fibros 15:34-42|
|Chen, Yong; Li, Wen; Jiang, Kai et al. (2016) Rapid T2 mapping of mouse heart using the carr-purcell-meiboom-gill sequence and compressed sensing reconstruction. J Magn Reson Imaging 44:375-82|
|Chen, Yong; Ye, Lei; Zhong, Jia et al. (2015) The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts With Postinfarct LV Remodeling. Cell Transplant 24:971-83|
|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|
|Goodnough, Candida L; Gao, Ying; Li, Xin et al. (2014) Lack of dystrophin results in abnormal cerebral diffusion and perfusion in vivo. Neuroimage 102 Pt 2:809-16|
|Bruckman, Michael A; Hern, Stephen; Jiang, Kai et al. (2013) Tobacco mosaic virus rods and spheres as supramolecular high-relaxivity MRI contrast agents. J Mater Chem B 1:1482-1490|
|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|
|Bruckman, Michael A; Yu, Xin; Steinmetz, Nicole F (2013) Engineering Gd-loaded nanoparticles to enhance MRI sensitivity via T(1) shortening. Nanotechnology 24:462001|
|Azam, Salman; Desjardins, Candida L; Schluchter, Mark et al. (2012) Comparison of velocity vector imaging echocardiography with magnetic resonance imaging in mouse models of cardiomyopathy. Circ Cardiovasc Imaging 5:776-81|
|Chen, Ya; Payne, Kevin; Perara, Vindya S et al. (2012) Inhibition of the sodium-calcium exchanger via SEA0400 altered manganese-induced T1 changes in isolated perfused rat hearts. NMR Biomed 25:1280-5|
Showing the most recent 10 out of 29 publications