The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model

Christopher Semsarian, Imran Ahmad, Michael Giewat, Dimitrios Georgakopoulos, Joachim P. Schmitt, Bradley K. McConnell, Steven Reiken, Ulrike Mende, Andrew R. Marks, David A. Kass, Christine E. Seidman, J. G. Seidman

Research output: Contribution to journalArticle

Abstract

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 αMHC403/+) bearing an Arg403Gln missense mutation in the α cardiac myosin heavy chain. We demonstrate that Ca2+ is reduced in the sarcoplasmic reticulum of αMHC403/+ mice, and levels of the sarcoplasmic reticulum Ca2+-binding protein calsequestrin are diminished in advance of changes in cardiac histology or morphology. Further evidence for dysregulation of sarcoplasmic reticulum Ca2+ in these animals is seen in their decreased expression of the ryanodine receptor Ca2+-release channel and its associated membrane proteins and in an increase in ryanodine receptor phosphorylation. Early administration of the L-type Ca2+ channel inhibitor diltiazem restores normal levels of these sarcoplasmic reticular proteins and prevents the development of pathology in αMHC403/+ mice. We conclude that disruption of sarcoplasmic reticulum Ca2+ homeostasis is an important early event in the pathogenesis of this disorder and suggest that the use of Ca2+ channel blockers in advance of established clinical disease could prevent hypertrophic cardiomyopathy caused by sarcomere protein gene mutations.

Original languageEnglish (US)
Pages (from-to)1013-1020
Number of pages8
JournalJournal of Clinical Investigation
Volume109
Issue number8
DOIs
StatePublished - Apr 29 2002

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Semsarian, C., Ahmad, I., Giewat, M., Georgakopoulos, D., Schmitt, J. P., McConnell, B. K., Reiken, S., Mende, U., Marks, A. R., Kass, D. A., Seidman, C. E., & Seidman, J. G. (2002). The L-type calcium channel inhibitor diltiazem prevents cardiomyopathy in a mouse model. Journal of Clinical Investigation, 109(8), 1013-1020. https://doi.org/10.1172/JCI200214677