Inactivation of cysteine 674 in the SERCA2 accelerates experimental aortic aneurysm
Inactivation of cysteine 674 in the SERCA2 accelerates experimental aortic aneurysm
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SERCA2 中半胱氨酸 674 的失活加速了实验性主动脉瘤的形成
DOI：
10.1016/j.yjmcc.2020.02.003
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发表时间：
2020-02-01
影响因子：
5
通讯作者：
Tong, Xiaoyong
中科院分区：
文献类型：
--
作者：
Que, Yumei;Shu, Xi;Tong, Xiaoyong
肌浆网/内质网Ca ~（2+）ATP酶2（SERCA 2）是维持细胞内钙稳态的重要酶。SERCA 2半胱氨酸674（C674）是高度保守的，其不可逆氧化在人类和小鼠主动脉瘤中上调，特别是在平滑肌细胞（SMC）中。SERCA 2及其氧化还原C674在主动脉瘤发展中的作用仍然是个谜。目的：探讨C674基因失活在主动脉瘤发生发展中的作用及其机制。方法和结果：使用SERCA 2 C674 S基因敲入（SKI）小鼠系，其中C674的一半被丝氨酸674（S674）取代，代表C674在主动脉瘤中的部分不可逆氧化，我们发现在主动脉SMC中，C674被5674取代导致SMC表型调节。在SKI平滑肌细胞中，细胞内钙的增加激活了钙依赖性钙调神经磷酸酶，从而促进了活化T淋巴细胞核因子（NFAT）和核因子κ B（NF κ B）的核转位，而抑制钙调神经磷酸酶则阻断了SMC的表型调节。此外，用5674替代C674加速了血管紧张素II诱导的主动脉瘤。结论：我们的研究结果表明，C674的失活通过引起细胞内钙的积累激活钙调神经磷酸酶介导的NFAT/NF κ B途径，导致SMC表型调节，加速主动脉瘤，这突出了C674氧化还原状态在主动脉瘤的发展中的重要性。
Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is vital to maintain intracellular calcium homeostasis. SERCA2 cysteine 674 (C674) is highly conservative and its irreversible oxidation is upregulated in human and mouse aortic aneurysms, especially in smooth muscle cells (SMCs). The contribution of SERCA2 and its redox C674 in the development of aortic aneurysm remains enigmatic. Objective: Our goal was to investigate the contribution of inactivation of C674 to the development of aortic aneurysm and the mechanisms involved. Approach and results: Using SERCA2 C674S knock-in (SKI) mouse line, in which half of C674 was substituted by serine 674 (S674) to represent partial irreversible oxidation of C674 in aortic aneurysm, we found that in aortic SMCs the replacement of C674 by 5674 resulted in SMC phenotypic modulation. In SKI SMCs, the increased intracellular calcium activated calcium-dependent calcineurin, which promoted the nuclear translocation of nuclear factor of activated T-lymphocytes (NFAT) and nuclear factor kappa-B (NF kappa B), while inhibition of calcineurin blocked SMC phenotypic modulation. Besides, the replacement of C674 by 5674 accelerated angiotensin II-induced aortic aneurysm. Conclusions: Our results indicate that the inactivation of C674 by causing the accumulation of intracellular calcium to activate calcineurin-mediated NFAT/NF kappa B pathways, resulted in SMC phenotypic modulation to accelerate aortic aneurysm, which highlights the importance of C674 redox state in the development of aortic aneurysms.