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Am J Physiol Heart Circ Physiol 279: H2414-H2423, 2000;
0363-6135/00 $5.00
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Vol. 279, Issue 5, H2414-H2423, November 2000

Altered hemodynamics in transgenic mice harboring mutant tropomyosin linked to hypertrophic cardiomyopathy

Christian C. Evans1, James R. Pena2, Ronald M. Phillips1, Mariappan Muthuchamy3, David F. Wieczorek3, R. John Solaro1, and Beata M. Wolska1,2

1 Departments of Physiology and Biophysics, and 2 College of Medicine, Section of Cardiology, The University of Illinois at Chicago, Chicago, Illinois 60612; and 3 Department of Microbiology, Biochemistry, and Molecular Biology, The University of Cincinnati, Cincinnati, Ohio 45267

We used transgenic (TG) mice overexpressing mutant alpha -tropomyosin [alpha -Tm(Asp175Asn)], linked to familial hypertrophic cardiomyopathy (FHC), to test the hypothesis that this mutation impairs cardiac function by altering the sensitivity of myofilaments to Ca2+. Left ventricular (LV) pressure was measured in anesthetized nontransgenic (NTG) and TG mice. In control conditions, LV relaxation was 6,970 ± 297 mmHg/s in NTG and 5,624 ± 392 mmHg/s in TG mice (P < 0.05). During beta -adrenergic stimulation, the rate of relaxation increased to 8,411 ± 323 mmHg/s in NTG and to 6,080 ± 413 mmHg/s in TG mice (P < 0.05). We measured the pCa-force relationship (pCa = -log [Ca2+]) in skinned fiber bundles from LV papillary muscles of NTG and TG hearts. In control conditions, the Ca2+ concentration producing 50% maximal force (pCa50) was 5.77 ± 0.02 in NTG and 5.84 ± 0.01 in TG myofilament bundles (P < 0.05). After protein kinase A-dependent phosphorylation, the pCa50 was 5.71 ± 0.01 in NTG and 5.77 ± 0.02 in TG myofilament bundles (P < 0.05). Our results indicate that mutant alpha -Tm(Asp175Asn) increases myofilament Ca2+-sensitivity, which results in decreased relaxation rate and blunted response to beta -adrenergic stimulation.

calcium; cardiomyopathy; hypertrophy; myocardial contraction


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