An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy.
Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)), when treated with calcineurin inhibitors or a K(+)-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca(2+) concentrations in wild-type cardiac myocytes; alphaMHC(403/+) myocytes failed to respond. Pretreatment with a Ca(2+)-channel antagonist abrogated diastolic Ca(2+) changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alphaMHC(403/+) mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca(2+) responses that initiate a hypertrophic response. These data define an important Ca(2+)-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.
Fatkin
D
D
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA.
McConnell
B K
BK
Mudd
J O
JO
Semsarian
C
C
Moskowitz
I G
IG
Schoen
F J
FJ
Giewat
M
M
Seidman
C E
CE
Seidman
J G
JG
D000818:Animals; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008914:Minoxidil / Q000494:pharmacology; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D012518:Sarcomeres / Q000737:chemistry; D016019:Survival Analysis; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D008914:Minoxidil; D016572:Cyclosporine; D018995:Myosin Heavy Chains; D002118:Calcium; D016559:Tacrolimus