消融与缺血再灌注损伤期间硝基氧化应激增加相关：对人类缺血性心肌病的影响。
Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy.
作者信息
Zhang Bo, Novitskaya Tatiana, Wheeler Debra G, Xu Zhaobin, Chepurko Elena, Huttinger Ryan, He Heng, Varadharaj Saradhadevi, Zweier Jay L, Song Yanna, Xu Meng, Harrell Frank E, Su Yan Ru, Absi Tarek, Kohr Mark J, Ziolo Mark T, Roden Dan M, Shaffer Christian M, Galindo Cristi L, Wells Quinn S, Gumina Richard J
机构信息
From the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute (B.Z., D.G.W., Z.X., R.H., H.H., S.V., J.L.Z.), Department of Physiology and Cell Biology (B.Z., J.L.Z., M.J.K., M.T.Z.), The Ohio State University, Columbus; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China (B.Z.); Department of Biostatistics (Y.S., M.X., F.E.H.), Division of Clinical Pharmacology, Department of Medicine (D.M.R., C.M.S.), Division of Cardiac Surgery, Department of Surgery (T.A.), Division of Cardiovascular Medicine (T. N., E. C., Y.R.S., D.R., C.L.G., Q.S.W, R.J.G.), Department of Pharmacology and Department of Pathology, Immunology, and Microbiology (R.J.G.), Vanderbilt University Medical Center, Nashville, TN.
出版信息
Circ Heart Fail. 2017 Feb;10(2). doi: 10.1161/CIRCHEARTFAILURE.116.003523.
BACKGROUND
Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM.
METHODS AND RESULTS
RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.
CONCLUSIONS
expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
背景
尽管缺血性心肌病（ICM）患者的继发性心血管事件有所增加，但ICM患者心脏中先天性心脏保护分子的表达尚未完全明确。因此，我们采用无偏倚的RNA测序方法来确定ICM患者心脏保护分子是否存在差异。
方法与结果
对人类对照和ICM左心室样本进行RNA测序分析，结果显示ICM患者的表达显著降低。 编码具有心脏保护作用的钾通道的Kir6.2亚基。我们使用野生型小鼠和基因缺陷（基因敲除）小鼠，研究了 表达对缺血再灌注损伤期间心脏功能的影响。缺血再灌注损伤后，基因敲除小鼠心脏中活性氧的产生高于野生型小鼠心脏。在缺血和再灌注期间连续测量左心室压力，结果显示，与野生型小鼠相比，基因敲除小鼠在再灌注期间舒张功能受损更严重。对关键钙调节蛋白的分析显示基因敲除小鼠存在显著差异。尽管舒张功能受损，但基因敲除小鼠的受磷蛋白丝氨酸16磷酸化增加，这种修饰导致受磷蛋白从肌浆网钙解离，从而增加肌浆网钙介导的钙再摄取。然而，基因敲除小鼠的肌浆网钙 - ATP酶的3 - 硝基酪氨酸修饰也增加，这种修饰不可逆地损害肌浆网钙功能，从而导致舒张功能障碍。
结论
人类ICM患者的 表达降低。缺乏 表达会增加心肌缺血再灌注损伤后过氧亚硝酸盐介导的关键钙处理蛋白肌浆网钙 - ATP酶的修饰，导致舒张功能受损。这些数据提示了ICM患者缺血诱导舒张功能障碍的机制。
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