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Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy

(2015) CIRCULATION RESEARCH. 117(9). p.793-803
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Abstract
Rationale: The regulation of calcium (Ca2+) homeostasis by -adrenergic receptor (AR) 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 AR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in AR-dependent regulation of Ca2+ handling has not yet been explicated fully. Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on AR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. Methods and Results: 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 AR-dependent regulation of Ca2+ homeostasis. Notably, S-nitrosylation of phospholamban consequent upon AR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca2+-ATPase and increases cytosolic Ca2+ transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca2+. During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca2+ overload. Conclusions: S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca2+-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca2+ homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.
Keywords
BRIDGE CYCLING KINETICS, TROPONIN-C MUTATIONS, S-NITROSYLATION, MYOCARDIAL-CONTRACTILITY, MOUSE HEARTS, PHOSPHOLAMBAN, PHOSPHORYLATION, TEMPERATURE, MYOCYTES, DENITROSYLATION, beta adrenergic, calcium, heart failure, myocardial contraction, nitric, oxide, receptors

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Citation

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MLA
Irie, Tomoya, et al. “Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.” CIRCULATION RESEARCH, vol. 117, no. 9, 2015, pp. 793–803.
APA
Irie, T., Sips, P., Kai, S., Kida, K., Ikeda, K., Hirai, S., … Ichinose, F. (2015). Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy. CIRCULATION RESEARCH, 117(9), 793–803.
Chicago author-date
Irie, Tomoya, Patrick Sips, Shinichi Kai, Kotaro Kida, Kohei Ikeda, Shuichi Hirai, Kasra Moazzami, et al. 2015. “Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.” CIRCULATION RESEARCH 117 (9): 793–803.
Chicago author-date (all authors)
Irie, Tomoya, Patrick Sips, Shinichi Kai, Kotaro Kida, Kohei Ikeda, Shuichi Hirai, Kasra Moazzami, Pawina Jiramongkolchai, Donald B Bloch, Paschalis-Thomas Doulias, Antonis A Armoundas, Masao Kaneki, Harry Ischiropoulos, Evangelia Kranias, Kenneth D Bloch, Jonathan S Stamler, and Fumito Ichinose. 2015. “Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.” CIRCULATION RESEARCH 117 (9): 793–803.
Vancouver
1.
Irie T, Sips P, Kai S, Kida K, Ikeda K, Hirai S, et al. Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy. CIRCULATION RESEARCH. 2015;117(9):793–803.
IEEE
[1]
T. Irie et al., “Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy,” CIRCULATION RESEARCH, vol. 117, no. 9, pp. 793–803, 2015.
@article{8506991,
  abstract     = {Rationale: The regulation of calcium (Ca2+) homeostasis by -adrenergic receptor (AR) 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 AR not only induces protein phosphorylation but also activates nitric oxide-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in AR-dependent regulation of Ca2+ handling has not yet been explicated fully. Objective: To elucidate the role of protein S-nitrosylation, a major transducer of nitric oxide bioactivity, on AR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. Methods and Results: 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 AR-dependent regulation of Ca2+ homeostasis. Notably, S-nitrosylation of phospholamban consequent upon AR stimulation is necessary for the inhibitory pentamerization of phospholamban, which activates sarcoplasmic reticulum Ca2+-ATPase and increases cytosolic Ca2+ transients. Coincident S-nitrosylation of cardiac troponin C decreases myocardial sensitivity to Ca2+. During chronic adrenergic stimulation, global reductions in cellular S-nitrosylation mitigate hypertrophic signaling resulting from Ca2+ overload. Conclusions: S-Nitrosylation operates in concert with phosphorylation to regulate many cardiac Ca2+-handling proteins, including phospholamban and cardiac troponin C, thereby playing an essential and previously unrecognized role in cardiac Ca2+ homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.},
  author       = {Irie, Tomoya and Sips, Patrick and Kai, Shinichi and Kida, Kotaro and Ikeda, Kohei and Hirai, Shuichi and Moazzami, Kasra and Jiramongkolchai, Pawina and Bloch, Donald B and Doulias, Paschalis-Thomas and Armoundas, Antonis A and Kaneki, Masao and Ischiropoulos, Harry and Kranias, Evangelia and Bloch, Kenneth D and Stamler, Jonathan S and Ichinose, Fumito},
  issn         = {0009-7330},
  journal      = {CIRCULATION RESEARCH},
  keywords     = {BRIDGE CYCLING KINETICS,TROPONIN-C MUTATIONS,S-NITROSYLATION,MYOCARDIAL-CONTRACTILITY,MOUSE HEARTS,PHOSPHOLAMBAN,PHOSPHORYLATION,TEMPERATURE,MYOCYTES,DENITROSYLATION,beta adrenergic,calcium,heart failure,myocardial contraction,nitric,oxide,receptors},
  language     = {eng},
  number       = {9},
  pages        = {793--803},
  title        = {Nitrosylation of calcium-handling proteins in cardiac adrenergic signaling and hypertrophy},
  url          = {http://dx.doi.org/10.1161/CIRCRESAHA.115.307157},
  volume       = {117},
  year         = {2015},
}

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