Abstract
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 Ca$^2+$ 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
Ca$^2+$ 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.
- 15331371
- adrene,
- animals,
- atpase,
- beta-agonists,
- calcium,
- cardiac,
- cardiovascular,
- cells,
- contraction,
- cultured,
- diastole,
- energy
- expression,
- female,
- gene
- isoproterenol,
- membrane
- metabolism,
- models,
- myocardial
- myocytes,
- of
- parvalbumins,
- potentials,
- rats,
- reproducibility
- results,
- reticulum,
- rgic
- sarcomeres,
- sarcoplasmic
- sprague-dawley,
- systole,
- techniques,
- transfer
- {c}a$^{2+}$-transporting
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