Project: Research project

Project Details


My long term goals are to understand the physiological regulation of
cardiac muscle contraction, particularly with respect to Ca and how it
changes with pathology. We have developed a number of techniques to
study in detail the regulation of [Ca] via individuals Ca transport
mechanisms in normal cardiac myocytes. It is also increasingly clear
that defects in cellular Ca regulation are intimately involved in the
process of cardiac hypertrophy and/or the transition of decompensation
during chronic pressure overload. In addition, several groups have used
cultured neonatal myocytes to study gene regulation in relation to
hypertrophy (since expression changes are relatively fast and their
environment can be easily controlled). The overall aim of the present
proposal is to combine the above approaches to provide a more
comprehensive picture of hypertrophic changes in cellular Ca regulation
(from the level of gene and protein expression to cellular Ca transport
and in vivo hemodynamics). We will study three experimental model offering different advantages and
disadvantages: 1) chronic aortic banding in adult rats at different times after banding
(e.g. 8 & 16 weeks), 2) a similar experimental model in rabbit and 3) cultured neonatal rat
ventricular myocytes. We will measure a) in vivo hemodynamics during chronic aortic banding
(e.g. LVEDP, dp/dt, relaxation time constant, T...), b) mRNA message and
protein levels for key proteins such as the SR Ca-pump, Na.Ca exchange,
Ca channels, MHCa/b and phospholamban and c) Ca transients, ion currents
and cell shortening in myocytes isolated from the same hearts using
specific protocols to determine the individual abilities of Ca transport
by the SR Ca-pump, Na/Ca exchange, Ica, mitochondria and the sarcolemmal
Ca-pump in intact cardiac myocytes. The specific questions to be addressed in banded rats (1-3.5), cultured
cells (4-6) and banded rabbits (7) are: 1) Does hypertrophy reduce SERCa2 message, protein and SR Ca transport
in intact cells? 2) Are there concomitant changes in Na/Ca exchange or other Ca transport
system? 3)Do Ca transport changes coincide with specific phases of hypertrophy
(e.g. transition to failure)? 4) Do changes in gene expression and Ca transport in cultured myocytes
mirror hypertrophy?
(e.g. after stimulation with phorbol esters or angiotensin II, vs
verapamil-induced arrest) 5) Are changes in Ca transport and hypertrophy prevented by verapamil or
ACE inhibitors? 6) Is regulation of the SR Ca-pump & Na/Ca exchange coordinated or can
changes be compensatory?
(e.g. when SR Ca transport in cultured cells is blocked by thapsigargin
do both systems increase?) 7) Do similar changes in Ca regulation occur in rabbit heart?
(Since the rat may not be the ideal model for human hypertrophy) Answer to these focused, yet comprehensive experimental questions will
contribute to our overall understanding of changes in cellular Ca
transport and their molecular basis for the development of compensatory
cardiac hypertrophy and the transition to failure.
Effective start/end date8/1/947/31/00


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $280,061.00
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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