Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart
Aberrant S-nitrosylation mediates calcium-triggered ventricular arrhythmia in the intact heart
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DOI：
10.1073/pnas.1210565109
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发表时间：
2012-10-30
影响因子：
11.1
通讯作者：
Laurita, Kenneth R.
中科院分区：
文献类型：
--
作者：
Cutler, Michael J.;Plummer, Bradley N.;Laurita, Kenneth R.
一氧化氮（NO）来源于神经元型一氧化氮合酶（NOS 1）的活性，参与肌浆网（SR）钙离子处理蛋白的S-亚硝基化。心脏ryanodine受体（RyR 2）的S-亚硝基化缺陷对分离的肌细胞中SR Ca 2+泄漏/火花具有可变的影响，可能取决于潜在的生理状态。然而，这种分子异常是否与完整心脏中的血管生成有因果关系仍不清楚。我们发现，在完整心脏中，NOS 1活性降低仅在心肌[Ca 2 +]升高的情况下增加Ca 2+介导的室性心律失常（i）。这些心律失常是由于自发SR Ca 2+释放增加引起的，这是由于RyR 2 S-亚硝基化（RyR 2-SNO）减少和RyR 2氧化（RyR-SOx）增加（即，来自黄嘌呤氧化还原酶活性的活性氧（ROS）增加）并且可以用黄嘌呤氧化还原酶（XOR）抑制来抑制（即，别嘌呤醇）或一氧化氮供体（即，S-亚硝基谷胱甘肽，GSNO）。令人惊讶的是，我们发现了NOS 1下调RyR 2磷酸化的证据，在Ca 2 +/钙调蛋白依赖性蛋白激酶（CaMKII）位点（S2814），表明亚硝基化和RyR 2磷酸化之间的分子串扰。最后，我们表明，亚硝基氧化还原不平衡，由于NOS 1活性降低敏感RyR 2的氧化应激的严重中毒表型。我们的研究结果表明，亚硝基氧化还原失衡是疾病条件下完整心脏室性心律失常的重要机制（即，升高的[Ca 2 +]（i）和氧化应激），恢复心脏亚硝基氧化还原平衡的疗法可以预防猝死。
Nitric oxide (NO) derived from the activity of neuronal nitric oxide synthase (NOS1) is involved in S-nitrosylation of key sarcoplasmic reticulum (SR) Ca2+ handling proteins. Deficient S-nitrosylation of the cardiac ryanodine receptor (RyR2) has a variable effect on SR Ca2+ leak/sparks in isolated myocytes, likely dependent on the underlying physiological state. It remains unknown, however, whether such molecular aberrancies are causally related to arrhythmogenesis in the intact heart. Here we show in the intact heart, reduced NOS1 activity increased Ca2+-mediated ventricular arrhythmias only in the setting of elevated myocardial [Ca2+](i). These arrhythmias arose from increased spontaneous SR Ca2+ release, resulting from a combination of decreased RyR2 S-nitrosylation (RyR2-SNO) and increased RyR2 oxidation (RyR-SOx) (i.e., increased reactive oxygen species (ROS) from xanthine oxidoreductase activity) and could be suppressed with xanthine oxidoreductase (XOR) inhibition (i.e., allopurinol) or nitric oxide donors (i.e., S-nitrosoglutathione, GSNO). Surprisingly, we found evidence of NOS1 down-regulation of RyR2 phosphorylation at the Ca2+/calmodulin-dependent protein kinase (CaMKII) site (S2814), suggesting molecular cross-talk between nitrosylation and phosphorylation of RyR2. Finally, we show that nitroso-redox imbalance due to decreased NOS1 activity sensitizes RyR2 to a severe arrhythmic phenotype by oxidative stress. Our findings suggest that nitroso-redox imbalance is an important mechanism of ventricular arrhythmias in the intact heart under disease conditions (i.e., elevated [Ca2+](i) and oxidative stress), and that therapies restoring nitroso-redox balance in the heart could prevent sudden arrhythmic death.