Genetic manipulation of calcium-handling proteins in cardiac myocytes. II. Mathematical modeling studies.
We developed a mathematical model specific to rat ventricular myocytes that includes electrophysiological representation, ionic homeostasis, force production, and sarcomere movement. We used this model to interpret, analyze, and compare two genetic manipulations that have been shown to increase myocyte relaxation rates, parvalbumin (Parv) de novo expression, and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) overexpression. The model was used to seek mechanistic insights into 1) the relative contribution of two mechanisms by which SERCA2a overexpression modifies Ca2+ sequestration, i.e., more pumps and an increase in the SERCA2a-to-phospholamban ratio, 2) the mechanisms behind postrest potentiation and how Parv and SERCA2a influence this response, and 3) why Parv myocytes retain their fast kinetics when endogenous SERCA2a is partially impaired by thapsigargin (a condition used to mimic diastolic dysfunction). The model was also utilized to predict whether Parv metal-binding characteristics might be modified to improve diastolic and systolic functions and whether Parv or SERCA2a might affect diastolic Ca2+ levels and myocyte energetics. One outcome of the model was to demonstrate a higher peak and total ATP consumption in SERCA2a myocytes and more even distribution of ATP throughout the cardiac cycle in Parv myocytes. This may have implications for failing hearts that are energetically compromised.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109-0622, USA.
Pierre
P
Coutu
Joseph M
JM
Metzger
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D003971:Diastole / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D010320:Parvalbumins / Q000235:genetics*; D051381:Rats; D015203:Reproducibility of Results; D012518:Sarcomeres / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013599:Systole / Q000502:physiology
D010320:Parvalbumins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium