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Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca 2+ Leak Independent of Luminal Ca 2+ and Trigger Ventricular Arrhythmias in Mice

2007; Lippincott Williams & Wilkins; Volume: 101; Issue: 6 Linguagem: Inglês

10.1161/circresaha.107.157552

1524-4571

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

Ion channel regulation and function

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 Ca2+ release directly or indirectly by buffering SR luminal Ca2+. 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 Ca2+ transients, cell shortening, L-type Ca2+ current, and SR volume were not significantly different in Casq2+/- and Casq2+/+ myocytes. However, in the presence of isoproterenol, SR Ca2+ leak was significantly increased in Casq2+/- myocytes (Casq2+/- 0.18+/-0.02 F(ratio) versus Casq2+/+ 0.11+/-0.01 F(ratio), n=57, 60; P<0.01), resulting in a significantly higher rate of spontaneous SR Ca2+ releases and triggered beats. SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction. As a result, the relationship between SR Ca2+ leak and SR luminal Ca2+ was significantly different between Casq2+/- and Casq2+/+ myocytes (P<0.01). Thus, even modest reductions in Casq2 increase SR Ca2+ leak and cause ventricular tachycardia susceptibility under stress. The underlying mechanism is likely the direct regulation of SR Ca2+ release channels by Casq2 rather than altered luminal Ca2+.