| First Author | Que Y | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 11 | Pages | 2305-2323 |
| PubMed ID | 33591571 | Mgi Jnum | J:340430 |
| Mgi Id | MGI:7529335 | Doi | 10.1111/bph.15411 |
| Citation | Que Y, et al. (2021) Inactivation of SERCA2 Cys(674) accelerates aortic aneurysms by suppressing PPARgamma. Br J Pharmacol 178(11):2305-2323 |
| abstractText | BACKGROUND AND PURPOSE: Inactivation of Cys(674) (C674) in the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) causes intracellular Ca(2+) accumulation, which activates calcineurin-mediated nuclear factor of activated T-lymphocytes (NFAT)/NF-kappaB 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 APPROACH: We 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 RESULTS: Inactivation of C674 inhibited the promoter activity and protein expression of PPARgamma, which could be reversed by inhibitors of calcineurin or NF-kappaB. In SKI SMCs, inhibition of NF-kappaB by pyrrolidinedithiocarbamic acid (PDTC) or overexpression of PPARgamma2 reversed the protein expression of SMC phenotypic modulation markers and inhibited cell proliferation, migration, and macrophage adhesion to SMCs. Pioglitazone, a PPARgamma agonist, blocked the activation of NFAT/NF-kappaB, 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 IMPLICATIONS: The inactivation of SERCA2 C674 promotes the development of aortic aneurysms by disrupting the balance between PPARgamma and NFAT/NF-kappaB. Our study highlights the importance of C674 redox status in regulating PPARgamma to maintain aortic homeostasis. |
