The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model.
Dominant mutations in sarcomere protein genes cause hypertrophic cardiomyopathy, an inherited human disorder with increased ventricular wall thickness, myocyte hypertrophy, and disarray. To understand the early consequences of mutant sarcomere proteins, we have studied mice (designated alphaMHC(403/+)) bearing an Arg403Gln missense mutation in the alpha cardiac myosin heavy chain. We demonstrate that Ca(2+) is reduced in the sarcoplasmic reticulum of alphaMHC(403/+) mice, and levels of the sarcoplasmic reticulum Ca(2+)-binding protein calsequestrin are diminished in advance of changes in cardiac histology or morphology. Further evidence for dysregulation of sarcoplasmic reticulum Ca(2+) in these animals is seen in their decreased expression of the ryanodine receptor Ca(2+)-release channel and its associated membrane proteins and in an increase in ryanodine receptor phosphorylation. Early administration of the L-type Ca(2+) channel inhibitor diltiazem restores normal levels of these sarcoplasmic reticular proteins and prevents the development of pathology in alphaMHC(403/+) mice. We conclude that disruption of sarcoplasmic reticulum Ca(2+) homeostasis is an important early event in the pathogenesis of this disorder and suggest that the use of Ca(2+) channel blockers in advance of established clinical disease could prevent hypertrophic cardiomyopathy caused by sarcomere protein gene mutations.
Semsarian
Christopher
C
Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Ahmad
Imran
I
Giewat
Michael
M
Georgakopoulos
Dimitrios
D
Schmitt
Joachim P
JP
McConnell
Bradley K
BK
Reiken
Steven
S
Mende
Ulrike
U
Marks
Andrew R
AR
Kass
David A
DA
Seidman
Christine E
CE
Seidman
J G
JG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002155:Calsequestrin / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004110:Diltiazem / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002155:Calsequestrin; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains; D004110:Diltiazem; D002118:Calcium