| First Author | Bai Y | Year | 2013 |
| Journal | Circ Res | Volume | 113 |
| Issue | 5 | Pages | 517-26 |
| PubMed ID | 23856523 | Mgi Jnum | J:213362 |
| Mgi Id | MGI:5584233 | Doi | 10.1161/CIRCRESAHA.113.301678 |
| Citation | Bai Y, et al. (2013) Phospholamban knockout breaks arrhythmogenic Ca(2)(+) waves and suppresses catecholaminergic polymorphic ventricular tachycardia in mice. Circ Res 113(5):517-26 |
| abstractText | RATIONALE: Phospholamban (PLN) is an inhibitor of cardiac sarco(endo)plasmic reticulum Ca(2)(+) ATPase. PLN knockout (PLN-KO) enhances sarcoplasmic reticulum Ca(2)(+) load and Ca(2)(+) leak. Conversely, PLN-KO accelerates Ca(2)(+) sequestration and aborts arrhythmogenic spontaneous Ca(2)(+) waves (SCWs). An important question is whether these seemingly paradoxical effects of PLN-KO exacerbate or protect against Ca(2)(+)-triggered arrhythmias. OBJECTIVE: We investigate the impact of PLN-KO on SCWs, triggered activities, and stress-induced ventricular tachyarrhythmias (VTs) in a mouse model of cardiac ryanodine-receptor (RyR2)-linked catecholaminergic polymorphic VT. METHODS AND RESULTS: We generated a PLN-deficient, RyR2-mutant mouse model (PLN-/-/RyR2-R4496C+/-) by crossbreeding PLN-KO mice with catecholaminergic polymorphic VT-associated RyR2-R4496C mutant mice. Ca(2)(+) imaging and patch-clamp recording revealed cell-wide propagating SCWs and triggered activities in RyR2-R4496C+/- ventricular myocytes during sarcoplasmic reticulum Ca(2)(+) overload. PLN-KO fragmented these cell-wide SCWs into mini-waves and Ca(2)(+) sparks and suppressed the triggered activities evoked by sarcoplasmic reticulum Ca(2)(+) overload. Importantly, these effects of PLN-KO were reverted by partially inhibiting sarco(endo)plasmic reticulum Ca(2)(+) ATPase with 2,5-di-tert-butylhydroquinone. However, Bay K, caffeine, or Li(+) failed to convert mini-waves to cell-wide SCWs in PLN-/-/RyR2-R4496C+/- ventricular myocytes. Furthermore, ECG analysis showed that PLN-KO mice are not susceptible to stress-induced VTs. On the contrary, PLN-KO protected RyR2-R4496C mutant mice from stress-induced VTs. CONCLUSIONS: Our results demonstrate that despite severe sarcoplasmic reticulum Ca(2)(+) leak, PLN-KO suppresses triggered activities and stress-induced VTs in a mouse model of catecholaminergic polymorphic VT. These data suggest that breaking up cell-wide propagating SCWs by enhancing Ca(2)(+) sequestration represents an effective approach for suppressing Ca(2)(+)-triggered arrhythmias. |
