Published online before print July 26, 2007, doi: 10.1161/CIRCRESAHA.107.157552
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Submitted on March 21, 2007
Revised on July 11, 2007
Accepted on July 18, 2007
Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca2+ Leak Independent of Luminal Ca2+ and Trigger Ventricular Arrhythmias in Mice
Nagesh Chopra ;
From the Oates Institute for Experimental Therapeutics and Division of Clinical Pharmacology, Departments of Medicine and Pharmacology (N.C., T.Y., I.H., B.C.K.); and Department of Pediatrics (P.J.K.), Vanderbilt University Medical Center, Nashville, Tenn; Cardiovascular Research Institute (T.H.), Washington Hospital Center, Washington DC; Laboratory for Mammalian Genes and Development (K.E., K.P.), National Institute of Child Health and Human Development/NIH, Bethesda, Md; Department of Medicine (B.A., L.R.J.), Krannert Institute of Cardiology, Indianapolis, Ind; and Department of Cell and Developmental Biology (C.F.-A.), University of Pennsylvania, Philadelphia.
* To whom correspondence should be addressed. E-mail: bjorn.knollmann{at}vanderbilt.edu.
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 Fratio versus Casq2+/+ 0.11±0.01 Fratio, 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+.
Key words: calsequestrin • ventricular arrhythmia • SR Ca2+ leak • SR Ca2+ release • catecholaminergic polymorphic ventricular tachycardia
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