Altered hemodynamics in transgenic mice harboring mutant tropomyosin linked to hypertrophic cardiomyopathy.
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 Ca(2+). 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 [Ca(2+)]) in skinned fiber bundles from LV papillary muscles of NTG and TG hearts. In control conditions, the Ca(2+) concentration producing 50% maximal force (pCa(50)) 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 pCa(50) 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 Ca(2+)-sensitivity, which results in decreased relaxation rate and blunted response to beta-adrenergic stimulation.
Evans
C C
CC
Departments of Physiology and Biophysics, Section of Cardiology, The University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Pena
J R
JR
Phillips
R M
RM
Muthuchamy
M
M
Wieczorek
D F
DF
Solaro
R J
RJ
Wolska
B M
BM
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects / Q000235:genetics*; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D010210:Papillary Muscles / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000235:genetics
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D014335:Tropomyosin; D017868:Cyclic AMP-Dependent Protein Kinases; D017301:Ca(2+) Mg(2+)-ATPase; D002118:Calcium