HAX-1 regulates SERCA2a oxidation and degradation.
HAX-1 regulates SERCA2a oxidation and degradation.
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HAX-1 调节 SERCA2a 氧化和降解
DOI：
10.1016/j.yjmcc.2017.11.014
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发表时间：
2018-01
影响因子：
5
通讯作者：
Kranias EG
中科院分区：
文献类型：
--
作者：
Bidwell PA;Liu GS;Nagarajan N;Lam CK;Haghighi K;Gardner G;Cai WF;Zhao W;Mugge L;Vafiadaki E;Sanoudou D;Rubinstein J;Lebeche D;Hajjar R;Sadoshima J;Kranias EG
缺血/再灌注损伤与收缩功能障碍和心肌细胞死亡增加有关。造血谱系底物-1-相关蛋白X-1（HAX-1）的过表达已显示出保护免受细胞损伤，但由于敲除小鼠的早期致死性，内源性HAX-1的功能仍然不清楚。在此，我们产生了心脏特异性和诱导型HAX-1缺陷模型，其揭示了HAX-1在缺血/再灌注损伤中在肌浆网/内质网Ca-ATP酶（SERCA 2a）调节中的意想不到的作用。尽管在成人心脏中消融HAX-1在非应激条件下未引起形态学改变，但其在缺血/再灌注损伤后减少了收缩恢复并增加了梗死面积。这些不利影响与SERCA 2a的损失增加有关。增强SERCA 2a降解不是由于钙蛋白酶和钙蛋白酶抑制素水平或钙蛋白酶活性的改变。相反，HAX-1过表达改善收缩恢复并维持SERCA 2a水平。在多个水平观察到HAX-1对SERCA 2a降解的调节作用，包括完整心脏、分离的心肌细胞和肌浆网微粒体。从机制上讲，HAX-1消融引起肌/内质网隔室活性氧产生增加，导致SERCA 2a氧化及其蛋白水解倾向。这种作用可能是由NAPDH氧化酶4（NOX 4）介导的，NOX 4是HAX-1的一种新的结合伴侣。因此，用夹竹桃苷抑制NOX消除了HAX-1消融在经受缺血/再灌注损伤的心脏中的作用。总之，我们的研究结果揭示了HAX-1在氧化应激和SERCA 2a降解的调节中的作用，暗示了其在钙稳态和细胞存活途径中的重要性。
Ischemia/reperfusion injury is associated with contractile dysfunction and increased cardiomyocyte death. Overexpression of the hematopoietic lineage substrate-1-associated protein X-1 (HAX-1) has been shown to protect from cellular injury but the function of endogenous HAX-1 remains obscure due to early lethality of the knockout mouse. Herein we generated a cardiac-specific and inducible HAX-1 deficient model, which uncovered an unexpected role of HAX-1 in regulation of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) in ischemia/reperfusion injury. Although ablation of HAX-1 in the adult heart elicited no morphological alterations under non-stress conditions, it diminished contractile recovery and increased infarct size upon ischemia/reperfusion injury. These detrimental effects were associated with increased loss of SERCA2a. Enhanced SERCA2a degradation was not due to alterations in calpain and calpastatin levels or calpain activity. Conversely, HAX-1 overexpression improved contractile recovery and maintained SERCA2a levels. The regulatory effects of HAX-1 on SERCA2a degradation were observed at multiple levels, including intact hearts, isolated cardiomyocytes and sarcoplasmic reticulum microsomes. Mechanistically, HAX-1 ablation elicited increased production of reactive oxygen species at the sarco/endoplasic reticulum compartment, resulting in SERCA2a oxidation and a predisposition to its proteolysis. This effect may be mediated by NAPDH oxidase 4 (NOX4), a novel binding partner of HAX-1. Accordingly, NOX inhibition with apocynin abrogated the effects of HAX-1 ablation in hearts subjected to ischemia/reperfusion injury. Taken together, our findings reveal a role of HAX-1 in the regulation of oxidative stress and SERCA2a degradation, implicating its importance in calcium homeostasis and cell survival pathways.
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影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
人类衰竭心脏中 micro-RNA765 的上调与蛋白磷酸酶抑制剂 1 的转录后调节和收缩力下降有关
影响因子：
18.2
作者：
Cai WF;Liu GS;Lam CK;Florea S;Qian J;Zhao W;Pritchard T;Haghighi K;Lebeche D;Lu LJ;Deng J;Fan GC;Hajjar RJ;Kranias EG
通讯作者：
Kranias EG
影响因子：
5.4
作者：
Kawaguchi, Y;Nakajima, K;Hirai, K
通讯作者：
Hirai, K
DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
影响因子：
64.8
作者：
Fu, Suneng;Yang, Ling;Li, Ping;Hofmann, Oliver;Dicker, Lee;Hide, Winston;Lin, Xihong;Watkins, Steven M.;Ivanov, Alexander R.;Hotamisligil, Goekhan S.
通讯作者：
Hotamisligil, Goekhan S.