Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice

Nagesh Chopra, Prince J. Kannankeril, Tao Yang, Thinn Hlaing, Izabela Holinstat, Kristen Ettensohn, Karl Pfeifer, Brandy Akin, Larry R. Jones, Clara Franzini-Armstrong, Björn C. Knollmann

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Abstract

Cardiac calsequestrin-null mice (Casq2) display catecholaminergic ventricular tachycardia akin to humans with CASQ2 mutations. However, the specific contribution of Casq2 deficiency to the arrhythmia phenotype is difficult to assess because Casq2 mice also show significant reductions in the sarcoplasmic reticulum (SR) proteins junctin and triadin-1 and increased SR volume. Furthermore, it remains unknown whether Casq2 regulates SR Ca release directly or indirectly by buffering SR luminal Ca. To address both questions, we examined heterozygous (Casq2) mice, which have a 25% reduction in Casq2 but no significant decrease in other SR proteins. Casq2 mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2 mice (n=31; P<0.05). Programmed stimulation induced significantly more ventricular tachycardia in Casq2 mice than in Casq2 mice. Field-stimulated Ca transients, cell shortening, L-type Ca current, and SR volume were not significantly different in Casq2 and Casq2 myocytes. However, in the presence of isoproterenol, SR Ca leak was significantly increased in Casq2 myocytes (Casq2 0.18±0.02 Fratio versus Casq2 0.11±0.01 Fratio, n=57, 60; P<0.01), resulting in a significantly higher rate of spontaneous SR Ca releases and triggered beats. SR luminal Ca measured using Mag-Fura-2 was not altered by Casq2 reduction. As a result, the relationship between SR Ca leak and SR luminal Ca was significantly different between Casq2 and Casq2 myocytes (P<0.01). Thus, even modest reductions in Casq2 increase SR Ca leak and cause ventricular tachycardia susceptibility under stress. The underlying mechanism is likely the direct regulation of SR Ca release channels by Casq2 rather than altered luminal Ca.

Original languageEnglish (US)
Pages (from-to)617-626
Number of pages10
JournalCirculation research
Volume101
Issue number6
DOIs
StatePublished - Sep 1 2007

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Keywords

  • Calsequestrin
  • Catecholaminergic polymorphic ventricular tachycardia
  • SR Ca leak
  • SR free luminal Ca
  • Ventricular arrhythmia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Chopra, N., Kannankeril, P. J., Yang, T., Hlaing, T., Holinstat, I., Ettensohn, K., Pfeifer, K., Akin, B., Jones, L. R., Franzini-Armstrong, C., & Knollmann, B. C. (2007). Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice. Circulation research, 101(6), 617-626. https://doi.org/10.1161/CIRCRESAHA.107.157552