Background and PurposeInactivation of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) causes intracellular Ca2+ accumulation, which activates calcineurin‐mediated nuclear factor of activated T‐lymphocytes (NFAT)/NF‐κB pathways, and results in the phenotypic modulation of smooth muscle cells (SMCs) to accelerate angiotensin II‐induced aortic aneurysms. Our goal was to investigate the mechanism involved.Experimental ApproachWe used heterozygous SERCA2 C674S knock‐in (SKI) mice, where half of C674 was substituted by serine, to mimic 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 ResultsInactivation of C674 inhibited the promoter activity and protein expression of PPARγ, which could be reversed by inhibitors of calcineurin or NF‐κB. In SKI SMCs, inhibition of NF‐κB by pyrrolidinedithiocarbamic acid (PDTC) or overexpression of PPARγ2 reversed the protein expression of SMC phenotypic modulation markers and inhibited cell proliferation, migration, and macrophage adhesion to SMCs. Pioglitazone, a PPARγ agonist, blocked the activation of NFAT/NF‐κB, reversed the protein expression of SMC phenotypic modulation markers, and inhibited cell proliferation, migration, and macrophage adhesion to SMCs in SKI SMCs. Furthermore, pioglitazone also ameliorated angiotensin II‐induced aortic aneurysms in SKI mice.Conclusions and ImplicationsThe inactivation of SERCA2 C674 promotes the development of aortic aneurysms 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.