Published online before print April 1, 2004, doi: 10.1161/01.RES.0000126923.46786.FD
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Submitted on December 22, 2003
Revised on March 17, 2004
Accepted on March 19, 2004
Parvalbumin Corrects Slowed Relaxation in Adult Cardiac Myocytes Expressing Hypertrophic Cardiomyopathy-Linked 
-Tropomyosin Mutations
Pierre Coutu ;
From the Departments of Biomedical Engineering (P.C.), Molecular and Integrative Physiology (C.N.B., E.G.F., J.M.M.), and Internal Medicine (S.M.D.), University of Michigan, Ann Arbor, Mich.
* To whom correspondence should be addressed. E-mail: metzgerj{at}umich.edu.
Hypertrophic cardiomyopathy mutations A63V and E180G in 
-tropomyosin (-Tm) have been shown to cause slow cardiac muscle relaxation. In this study, we used two complementary genetic strategies, gene transfer in isolated rat myocytes and transgenesis in mice, to ascertain whether parvalbumin (Parv), a myoplasmic calcium buffer, could correct the diastolic dysfunction caused by these mutations. Sarcomere shortening measurements in rat cardiac myocytes expressing the -Tm A63V mutant revealed a slower time to 50% relengthening (T50R: 44.2±1.4 ms in A63V, 36.8±1.0 ms in controls; n=96 to 108; P<0.001) when compared with controls. Dual gene transfer of -Tm A63V and Parv caused a marked decrease in T50R (29.8±1.0 ms). However, this increase in relaxation rate was accompanied with a decrease in shortening amplitude (114.6±4.4 nm in A63+Parv, 137.8±5.3 nm in controls). Using an asynchronous gene transfer strategy, Parv expression was reduced (from 
0.12 to 0.016 mmol/L), slow relaxation redressed, and shortening amplitude maintained (T50R=33.9±1.6 ms, sarcomere shortening amplitude=132.2±7.0 nm in A63V+PVdelayed; n=56). Transgenic mice expressing the E180G -Tm mutation and mice expressing Parv in the heart were crossed. In isolated adult myocytes, the -Tm mutation alone (E180G+/PV-) had slower sarcomere relengthening kinetics than the controls (T90R: 199±7 ms in E180G+/PV-, 130±4 ms in E180G-/PV-; n=71 to 72), but when coexpressed with Parv, cellular relaxation was faster (T90R: 36±4 ms in E180G+/PV+). Collectively, these findings show that slow relaxation caused by -Tm mutants can be corrected by modifying calcium handling with Parv.
Key words: tropomyosin • parvalbumin • hypertrophic cardiomyopathy • diastolic dysfunction • gene transfer
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