Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium-handling

Andrew P. Landstrom, Cherisse A. Kellen, Sayali S. Dixit, Ralph J. Van Oort, Alejandro Garbino, Noah Weisleder, Jianjie Ma, Xander H.T. Wehrens, Michael J. Ackerman

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Background-Junctophilin-2 (JPH2), a protein expressed in the junctional membrane complex, is necessary for proper intracellular calcium (Ca 2+) signaling in cardiac myocytes. Downregulation of JPH2 expression in a model of cardiac hypertrophy was recently associated with defective coupling between plasmalemmal L-type Ca2+ channels and sarcoplasmic reticular ryanodine receptors. However, it remains unclear whether JPH2 expression is altered in patients with hypertrophic cardiomyopathy (HCM). In addition, the effects of downregulation of JPH2 expression on intracellular Ca2+ handling are presently poorly understood. We sought to determine whether loss of JPH2 expression is noted among patients with HCM and whether expression silencing might perturb Ca2+ handling in a prohypertrophic manner. Methods and Results-JPH2 expression was reduced in flash-frozen human cardiac tissue procured from patients with HCM compared with ostensibly healthy traumatic death victims. Partial silencing of JPH2 expression in HL-1 cells by a small interfering RNA probe targeted to murine JPH2 mRNA (shJPH2) resulted in myocyte hypertrophy and increased expression of known markers of cardiac hypertrophy. Whereas expression levels of major Ca2+-handling proteins were unchanged, shJPH2 cells demonstrated depressed maximal Ca 2+ transient amplitudes that were insensitive to L-type Ca 2+ channel activation with JPH2 knockdown. Further, reduced caffeine-triggered sarcoplasmic reticulum store Ca2+ levels were observed with potentially increased total Ca2+ stores. Spontaneous Ca2+ oscillations were elicited at a higher extracellular [Ca 2+] and with decreased frequency in JPH2 knockdown cells. Conclusions-Our results show that JPH2 levels are reduced in patients with HCM. Reduced JPH2 expression results in reduced excitation-contraction coupling gain as well as altered Ca2+ homeostasis, which may be associated with prohypertrophic remodeling.

Original languageEnglish (US)
Pages (from-to)214-223
Number of pages10
JournalCirculation: Heart Failure
Volume4
Issue number2
DOIs
StatePublished - Mar 1 2011

Keywords

  • Calcium
  • Hypertrophic cardiomyopathy
  • JPH2
  • Junctophilin
  • Ryanodine receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Landstrom, A. P., Kellen, C. A., Dixit, S. S., Van Oort, R. J., Garbino, A., Weisleder, N., Ma, J., Wehrens, X. H. T., & Ackerman, M. J. (2011). Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium-handling. Circulation: Heart Failure, 4(2), 214-223. https://doi.org/10.1161/CIRCHEARTFAILURE.110.958694