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Am J Physiol Heart Circ Physiol 293: H1705-H1713, 2007. First published June 1, 2007; doi:10.1152/ajpheart.00232.2007
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Parvalbumin isoforms differentially accelerate cardiac myocyte relaxation kinetics in an animal model of diastolic dysfunction

David W. Rodenbaugh,1 Wang Wang,1 Jennifer Davis,1 Terri Edwards,1 James D. Potter,2 and Joseph M. Metzger1

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 {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 Mg2+ 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 Mg2+ affinity and ~200% greater Ca2+ 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 ~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.

gene transfer; mechanical relaxation



Address for reprint requests and other correspondence: J. M. Metzger, Dept. of Molecular and Integrative Physiology, 7730 Medical Science II, Univ. of Michigan, 1301 E. Catherine St., Ann Arbor, MI 48109-0622 (e-mail: metzgerj{at}umich.edu)







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