期刊
CIRCULATION RESEARCH
卷 101, 期 6, 页码 617-626出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.157552
关键词
calsequestrin; ventricular arrhythmia; SR Ca2+ leak; SR free luminal Ca2+; catecholaminergic polymorphic ventricular tachycardia
资金
- Intramural NIH HHS Funding Source: Medline
- NHLBI NIH HHS [HL46681, HL48093, HL71670, HL88635, HL28556] Funding Source: Medline
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+.
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