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Inactivation of SERCA2 Cys674 accelerates aortic aneurysms by suppressing PPARγ
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  • Yumei Que,
  • Xi Shu,
  • Langtao Wang,
  • Sai Wang,
  • Pingping Hu,
  • Xiaoyong Tong
Yumei Que
Innovative Drug Research Center
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Xi Shu
Innovative Drug Research Center
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Langtao Wang
Innovative Drug Research Center
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Sai Wang
Innovative Drug Research Center
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Pingping Hu
Innovative Drug Research Center
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Xiaoyong Tong
Innovative Drug Research Center
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Abstract

Background and Purpose Inactivation of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) by causing the accumulation of intracellular Ca2+ to activate calcineurin-mediated nuclear factor of activated T-lymphocytes (NFAT)/NF-κB pathways, resulted in the phenotypic modulation of smooth muscle cells (SMCs) to accelerate angiotensin II-induced aortic aneurysm. Our goal was to investigate the mechanism involved. Experimental Approach We used heterozygous SERCA2 C674S knock-in (SKI) mice, where half of C674 was substituted by serine, to represent partial irreversible oxidation of C674. The aortas of SKI mice and their littermate wild-type mice were collected for RNA sequencing, cell culture, protein expression, luciferase activity and aortic aneurysm analysis. KEY RESULTS Inactivation of C674 inhibited the promoter activity and protein expression of PPARγ, which could be reversed by inhibitors of calcineurin or NF-κB. Overexpression of PPARγ2 inhibited the phenotypic modulation of SKI SMCs. Pioglitazone, the activator of PPARγ, blocked the activation of NFAT/NF-κB, inhibited SMC phenotypic modulation, and ameliorated angiotensin II-induced aortic aneurysms in SKI mice. CONCLUSIONS AND IMPLICATIONS The inactivation of SERCA2 C674 promotes the development of aortic aneurysm by disrupting the balance between PPARγ and NFAT/NF-κB. Our study highlights the importance of C674 redox status in regulating PPARγ to maintain aortic homeostasis.

Peer review status:UNDER REVIEW

26 Aug 2020Submitted to British Journal of Pharmacology
26 Aug 2020Assigned to Editor
26 Aug 2020Submission Checks Completed
10 Sep 2020Reviewer(s) Assigned