Abstract 11390: Increased Spontaneous Ca2+ Release Events and Na+-ca2+ Exchanger Activity Induce Ventricular Arrhythmias in Sorcin-Knockout Mice Under Beta-Adrenergic Stimulation
Sorcin is a penta-EF-hand Ca2+ binding protein that in the heart may act as a cytosolic Ca2+ sweeper by inhibiting the opening of ryanodine receptors (RyRs), stimulating SERCA2a and Na+-Ca2+ exchanger (NCX) activity, and accelerating L-type Ca2+ channel inactivation, but its physiological role remains unclear. Here, we generated a sorcin knockout (sorcin KO) mouse by ablating the sorcin-encoding gene SRI and investigated sorcin’s role on cardiac performance in health and disease. In basal conditions, WT and sorcin KO cardiomyocytes displayed similar Ca2+ spark frequency (0.25±0.12 vs. 0.10±0.04 sparks/(100μm•s), respectively, p=0.28, 8-9 cells/group), but stimulation with 300 nM isoproterenol (Iso) increased spark frequency in sorcin KO to a higher extent than in WT cells (1.43±0.29 vs. 0.51±0.15, p<0.05, 6-15 cells/group). Sorcin KO cardiomyocytes had higher RyR-mediated SR Ca2+ leak in 0 Na+- 0 Ca2+ solution (0.20±0.03 vs. 0.11±0.02, p<0.01, 13 cells /group), and tended to have more spontaneous Ca2+ waves than WT (0.15±0.02 vs. 0.072±0.02 Hz, p=0.078, 31 KO cells, 15 WT cells). A 2.2-fold NCX expression detected by Western blots and a faster decay of the caffeine-induced Ca2+ transient (τ = 2100±217 vs. 3823±667ms, p<0.05, 9 cells/group) in sorcin KO cardiomyocytes reflected higher NCX activity. Administration of Iso 2 mg/kg + caffeine 120 mg/kg in anesthetized sorcin KO and WT mice induced premature ventricular contractions (8/12 vs. 2/12 mice), ventricular tachycardia (10/12 vs. 2/12), bidirectional ventricular tachycardia (3/12 vs. 0/12), and sudden cardiac arrest (4/12 vs. 0/12). Survival rate in sorcin KO mice was significantly lower than WT after transverse aortic constriction (12% vs. 96% after 2 weeks, n=24 mice). Thus, stressful conditions break the delicate equilibrium in which sorcin KO cells operate. In cardiomyocytes of the double sorcin and phospholamban KO mice, there was a increase in spark frequency in basal condition compared with WT (p<0.05), sorcin KO (p<0.05) and PLN KO. In conclusion, the loss of sorcin in the heart goes apparently “silent” under basal conditions, but results in abnormal [Ca2+]i handling, increased NCX activity, arrhythmogenicity under sympathetic stimulation and enhanced vulnerability to stress.
- © 2013 by American Heart Association, Inc.