S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.
Circ Res
; 117(9): 793-803, 2015 Oct 09.
Article
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| MEDLINE
| ID: mdl-26259881
ABSTRACT
RATIONALE The regulation of calcium (Ca(2+)) homeostasis by ß-adrenergic receptor (ßAR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the ßAR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in ßAR-dependent regulation of Ca(2+) handling has not yet been explicated fully. OBJECTIVE:
To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on ßAR-dependent alterations in cardiomyocyte Ca(2+) handling and hypertrophy. METHODS ANDRESULTS:
Using transgenic mice to titrate the levels of protein S-nitrosylation, we uncovered major roles for protein S-nitrosylation, in general, and for phospholamban and cardiac troponin C S-nitrosylation, in particular, in ßAR-dependent regulation of Ca(2+) homeostasis. Notably, S-nitrosylation of phospholamban consequent upon ßAR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca(2+)-ATPase and increases cytosolic Ca(2+) transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca(2+). During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca(2+) overload.CONCLUSIONS:
S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca(2+)-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca(2+) homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.Palabras clave
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1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Calcio
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Receptores Adrenérgicos beta
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Miocitos Cardíacos
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Miocardio
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Óxido Nítrico
Límite:
Animals
Idioma:
En
Revista:
Circ Res
Año:
2015
Tipo del documento:
Article