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Parvalbumin isoforms differentially accelerate cardiac myocyte relaxation kinetics in an animal model of diastolic dysfunction

¹Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and ²Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida

Submitted 22 February 2007 ; accepted in final form 31 May 2007

The cytosolic Ca²⁺/Mg²⁺-binding protein -parvalbumin (-Parv) has been shown to accelerate cardiac relaxation; however, beyond an optimal concentration range, -Parv can also diminish contractility. Mathematical modeling suggests that increasing Parv's Mg²⁺ affinity may lower the effective concentration of Parv ([Parv]) to speed relaxation and, thus, limit Parv-mediated depressed contraction. Naturally occurring /-Parv isoforms show divergence in amino acid primary structure (57% homology) and cation-binding affinities, with -Parv having an estimated 16% greater Mg²⁺ affinity and 200% greater Ca²⁺ affinity than -Parv. We tested the hypothesis that, at the same or lower estimated [Parv], mechanical relaxation rate would be more significantly accelerated by -Parv than by -Parv. Dahl salt-sensitive (DS) rats were used as an experimental model of diastolic dysfunction. Relaxation properties were significantly slowed in adult cardiac myocytes isolated from DS rats compared with controls: time from peak contraction to 50% relaxation was 57 ± 2 vs. 49 ± 2 (SE) ms (P < 0.05), validating this model system. DS cardiac myocytes were subsequently transduced with - or -Parv adenoviral vectors. Upon Parv gene transfer, -Parv caused significantly faster relaxation than -Parv (P < 0.05), even though estimated [-Parv] was 10% of [-Parv]. This comparative analysis showing distinct functional outcomes raises the prospect of utilizing naturally occurring Parv variants to address disease-associated slowed cardiac relaxation.

gene transfer; mechanical relaxation

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