S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.
S-Nitrosylation of Calcium-Handling Proteins in Cardiac Adrenergic Signaling and Hypertrophy.
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DOI：
10.1161/circresaha.115.307157
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发表时间：
2015-10-09
影响因子：
20.1
通讯作者：
Ichinose F
中科院分区：
文献类型：
--
作者：
Irie T;Sips PY;Kai S;Kida K;Ikeda K;Hirai S;Moazzami K;Jiramongkolchai P;Bloch DB;Doulias PT;Armoundas AA;Kaneki M;Ischiropoulos H;Kranias E;Bloch KD;Stamler JS;Ichinose F
β-肾上腺素能受体(β-AR)激活对钙离子(Ca~(2+))稳态的调节为交感神经调节心肌功能提供了必要的基础，也为理解导致肥大信号和心力衰竭的分子事件提供了基础。交感神经刺激β受体不仅诱导蛋白磷酸化，而且激活一氧化氮(NO)依赖的信号转导，从而调节心肌收缩能力。然而，NO在β受体依赖的钙通道调节中的作用尚未完全阐明。目的：阐明NO的主要转导蛋白S亚硝化在心肌细胞钙转运和肥大过程中β受体依赖性改变中的作用。利用转基因小鼠来滴定SNO蛋白的水平，我们普遍发现了蛋白S-亚硝化，特别是磷蛋白和心肌肌钙蛋白C S-亚硝化在βAR依赖的钙稳态调节中的主要作用。值得注意的是，βAR刺激后引起的PLN的S亚硝化是其抑制PLN五聚化所必需的，该五聚体激活肌浆网钙-三磷酸腺苷酶(SERCA2a)并增加胞浆钙瞬变。CTNC的S-亚硝化反应降低心肌对钙离子的敏感性。在慢性肾上腺素能刺激过程中，细胞内S亚硝化的整体减少减轻了钙超载引起的肥大信号。S-亚硝化与磷酸化协同作用，调节包括PLN和CTNC在内的许多心肌钙调节蛋白，从而在心肌钙稳态中发挥重要的和先前未知的作用。操纵S-亚硝化水平可能被证明是治疗心力衰竭的方法。
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. To elucidate the role of protein S-nitrosylation, a major transducer of NO bioactivity, on βAR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. 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. 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.