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.