Nitric Oxide Modulates Ca 2+ Leak and Arrhythmias via S-Nitrosylation of CaMKII

作者：Amelia Power, Esther Udo Asamudo, Luke P. I. Worthington, Chidera C. Alim, Raquel E. Parackal, Rachel S. Wallace, Obialunanma V. Ebenebe, Joan Heller Brown, Mark J. Kohr, Donald M. Bers, Jeffrey R. Erickson · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.123.323571 · 被引用次数：21 · 研究领域：Nitric Oxide and Endothelin Effects、Cardiac electrophysiology and arrhythmias、Cardiac Ischemia and Reperfusion

BACKGROUND: Nitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca 2+ release via S -nitrosylation of CaMKIIδ (Ca 2+ /calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of S -nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca 2+ handling and arrhythmogenesis before and during β-adrenergic receptor stimulation. METHODS: We measured Ca 2+ -handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the S -nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S -nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L). RESULTS: Both WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca 2+ transient response as well as increased Ca 2+ spark frequency. However, the increase in Ca 2+ spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca 2+ sparks and waves was mimic...