Nitric Oxide Modulates Ca 2+ Leak and Arrhythmias via S-Nitrosylation of CaMKII.
| Autor: | Power AS; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.).; Department of Physiology, University of Auckland, New Zealand (A.S.P.)., Asamudo EU; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.).; Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)., Worthington LPI; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)., Alim CC; Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)., Parackal RE; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)., Wallace RS; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.)., Ebenebe OV; Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (O.V.E., M.J.K.)., Heller Brown J; Department of Pharmacology, University of California, San Diego, La Jolla (J.H.B.)., Kohr MJ; Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (O.V.E., M.J.K.)., Bers DM; Department of Pharmacology, University of California, Davis (E.U.A., C.C.A., D.M.B.)., Erickson JR; Department of Physiology and HeartOtago, University of Otago, Dunedin, New Zealand (A.S.P., E.U.A., L.P.I.W., R.E.P., R.S.W., J.R.E.). |
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| Jazyk: | angličtina |
| Zdroj: | Circulation research [Circ Res] 2023 Dec 08; Vol. 133 (12), pp. 1040-1055. Date of Electronic Publication: 2023 Nov 14. |
| DOI: | 10.1161/CIRCRESAHA.123.323571 |
| Abstrakt: | 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 mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events. Conclusions: We conclude that prior S -nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor-induced arrhythmias, but that S -nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting. Competing Interests: Disclosures None. |
| Databáze: | MEDLINE |
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