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Inactivation of cysteine 674 in the SERCA2 accelerates experimental aortic aneurysm

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 contrib...

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Published in:Journal of molecular and cellular cardiology 2020-02, Vol.139, p.213-224
Main Authors: Que, Yumei, Shu, Xi, Wang, Langtao, Hu, Pingping, Wang, Sai, Xiong, Rui, Liu, Jin, Chen, Hao, Tong, Xiaoyong
Format: Article
Language:English
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Summary: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. •SERCA2 is essential in maintaining aortic homeostasis.•Increased SERCA2 C674 irreversible oxidation in aortic aneurysms•Inactivation of C674 aggravates angiotensin II-induced aortic aneurysms.•Inactivation of C674 promotes SMC phenotypic modulation by activating calcineurin.
ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2020.02.003