S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy
Rationale: The regulation of calcium (Ca2+) homeostasis by beta-adrenergic receptor (βAR) 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 βAR not only induces protein phosphorylation but also activates nitric oxide (NO)-dependent signaling, which modulates cardiac contractility. Nonetheless, the role of NO in βAR-dependent regulation of Ca2+ handling has not yet been explicated fully.
Objective: To elucidate the role of protein S-nitrosylation, a major transducer of NO bioactivity, on βAR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy.
Methods and Results: Using transgenic mice to titrate the levels of protein SNO, we uncovered major roles for protein S-nitrosylation generally, and for phospholamban (PLN) and cardiac troponin C (cTnC) S-nitrosylation in particular, in βAR-dependent regulation of Ca2+ homeostasis. Notably, S-nitrosylation of PLN consequent upon βAR stimulation is necessary for its inhibitory pentamerization of PLN, which activates sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and increases cytosolic Ca2+ transients. Coincident S-nitrosylation of cTnC 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 PLN and cTnC, thereby playing an essential and previously unrecognized role in cardiac Ca2+ homeostasis. Manipulation of the S-nitrosylation level may prove therapeutic in heart failure.
- Received July 6, 2015.
- Revision received August 5, 2015.
- Accepted August 10, 2015.