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

The cytosolic Ca(2+)/Mg(2+)-binding protein alpha-parvalbumin (alpha-Parv) has been shown to accelerate cardiac relaxation; however, beyond an optimal concentration range, alpha-Parv can also diminish contractility. Mathematical modeling suggests that increasing Parv's Mg(2+) affinity may lower the effective concentration of Parv (Parv]) to speed relaxation and, thus, limit Parv-mediated depressed contraction. Naturally occurring alpha/beta-Parv isoforms show divergence in amino acid primary structure (57% homology) and cation-binding affinities, with beta-Parv having an estimated 16% greater Mg(2+) affinity and approximately 200% greater Ca(2+) affinity than alpha-Parv. We tested the hypothesis that, at the same or lower estimated Parv], mechanical relaxation rate would be more significantly accelerated by beta-Parv than by alpha-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 alpha- or beta-Parv adenoviral vectors. Upon Parv gene transfer, beta-Parv caused significantly faster relaxation than alpha-Parv (P < 0.05), even though estimated beta-Parv] was approximately 10% of alpha-Parv]. This comparative analysis showing distinct functional outcomes raises the prospect of utilizing naturally occurring Parv variants to address disease-associated slowed cardiac relaxation.