Predicting the Effects of Stretch-Activated Reactive Oxygen Species Signaling on Cardiac Excitation-Contraction Coupling




Limbu, Sarita

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Calcium (Ca2+) is an important second messenger in cardiac myocytes and regulates the excitation-contraction (EC) coupling, the process which converts electrical signal into the mechanical contraction of the myocytes. Regulation of the Ca2+ released from sarcoplasmic reticulum (SR), the Ca2+ store in cardiac myocytes, via ryanodine receptor 2 (RyR2), the Ca2+ release channel in the SR, is crucial for physiological functioning of the myocyte. Reactive oxygen species (ROS) regulate cardiac Ca2+ signaling by oxidizing and increasing the open probability of RyR2s. Stretching of a cardiac myocyte has been shown to induce Nox2 mediated ROS production in a process termed X-ROS signaling that abruptly increases the Ca2+ released from the SR. A computational model of the rat cardiac ventricular myocyte with X-ROS signaling was developed. The model was used to investigate the underlying mechanisms of regulation of EC coupling by X-ROS. The X-ROS dependent effects of oxidative stress on EC coupling during pathology, such as heart failure, were studied. Stretching a cardiomyocyte elevates the intracellular Ca2+ concentration via X-ROS but on the other hand, the increase in affinity of troponin for Ca2+ increases the Ca2+ buffering and decreases the free cytosolic Ca2+ concentration. The X-ROS mediated effects of length dependent change in Ca2+ binding affinity of troponin and its subsequent effects on Ca2+ dynamics were also studied. The model was integrated into the spatial model and the spatial model of a ventricular myocyte model with X-ROS signaling was developed to understand various spatial components which would contribute towards abnormalities such as arrhythmia during pathologies.



Bioinformatics, Calcium, Cardiac, ROS, Stretch