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 S674 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 (NFκB), while inhibition of calcineurin blocked SMC phenotypic modulation. Besides, the replacement of C674 by S674 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/NFκB pathways, resulted in SMC phenotypic modulation to accelerate aortic aneurysm, which highlights the importance of C674 redox state in the development of aortic aneurysms.

中文翻译：

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SERCA2中的半胱氨酸674失活会加速实验性主动脉瘤。

肌浆/内质网Ca2 + ATPase 2（SERCA2）对维持细胞内钙稳态至关重要。SERCA2半胱氨酸674（C674）非常保守，其不可逆氧化在人和小鼠的主动脉瘤，尤其是平滑肌细胞（SMC）中被上调。SERCA2及其氧化还原C674在主动脉瘤发展中的贡献仍然是谜。目的：我们的目标是研究C674失活对主动脉瘤发展的作用及其机制。方法和结果：使用SERCA2 C674S敲入（SKI）小鼠品系，其中C674的一半被丝氨酸674（S674）取代以代表主动脉瘤中C674的部分不可逆氧化，我们发现在主动脉SMC中替代了C674由S674引起的SMC表型调节。在SKI SMC中，增加的细胞内钙激活钙依赖性钙调神经磷酸酶，从而促进活化的T淋巴细胞（NFAT）和核因子kappa-B（NFκB）的核因子的核易位，而抑制钙调神经磷酸酶则阻止了SMC表型调节。此外，用S674替代C674可加速血管紧张素II诱导的主动脉瘤。结论：我们的结果表明，通过引起细胞内钙的积聚来激活钙调神经磷酸酶介导的NFAT /NFκB途径，C674的失活导致SMC表型调节以加速主动脉瘤，这突出了C674氧化还原状态在主动脉发展中的重要性。动脉瘤。促进活化的T淋巴细胞（NFAT）的核因子和核因子kappa-B（NFκB）的核易位，而抑制钙调神经磷酸酶则阻止了SMC表型调节。此外，用S674替代C674可加速血管紧张素II诱导的主动脉瘤。结论：我们的结果表明，通过引起细胞内钙的积聚来激活钙调神经磷酸酶介导的NFAT /NFκB途径，C674的失活导致SMC表型调节以加速主动脉瘤，这突出了C674氧化还原状态在主动脉发展中的重要性。动脉瘤。促进活化的T淋巴细胞（NFAT）的核因子和核因子kappa-B（NFκB）的核易位，而抑制钙调神经磷酸酶则阻止了SMC表型调节。此外，用S674替代C674可加速血管紧张素II诱导的主动脉瘤。结论：我们的结果表明，通过引起细胞内钙的积聚来激活钙调神经磷酸酶介导的NFAT /NFκB途径，C674的失活导致SMC表型调节以加速主动脉瘤，这突出了C674氧化还原状态在主动脉发展中的重要性。动脉瘤。