Prostacyclin and PPARα agonists control vascular smooth muscle cell apoptosis and phenotypic switch through distinct 14-3-3 isoforms.
Prostacyclin and PPARα agonists control vascular smooth muscle cell apoptosis and phenotypic switch through distinct 14-3-3 isoforms.
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DOI：
10.1371/journal.pone.0069702
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wu KK
中科院分区：
文献类型：
--
作者：
Chen YC;Chu LY;Yang SF;Chen HL;Yet SF;Wu KK
我们推测前列环素通过激活过氧化物酶体增殖物激活受体α(PPARα)和14-3-3上调来保护血管平滑肌细胞免受凋亡和表型转换的影响。在此，我们发现，用产生PGI2的载体Ad-COPI转导大鼠主动脉VSMC A-10，可减弱H_2O_2诱导的细胞凋亡，并选择性增加14-3-3β和14-3-3θ的表达。卡巴前列环素(CPGI2)和Wy14,643也发挥了类似的作用。PPARα拮抗剂MK886可阻断PGI2的作用，而PPARδ拮抗剂GSK3787则无此作用。PPARα可上调14-3-3β和θ的表达，并减弱过氧化氢诱导的细胞凋亡。Caspase3抑制剂可抑制过氧化氢诱导的14-3-3β降解，但不能抑制14-3-3θ的降解。此外，14-3-3β过表达减少，而14-3-3θ过表达无明显变化，14-3-3β加剧了细胞的凋亡。H_2O_2处理的A-10细胞VSMC收缩蛋白和血清反应因子(SRF)降低，而caspase-3抑制剂可同时阻止这种作用。相反，PGI2阻止了H_2O_2诱导的Sm22α和Calponin-1的降解，而不影响SRF。CPGI2和Wy14,643也有效地阻断了生长因子(GFS)诱导的VSMC表型转换。GFS抑制14-3-3β，θ，ε和η亚型，cPGI2可阻止β，θ和η的下降，但不能阻止ε的下降。14-3-3θsiRNA阻断了cPGI2对Sm22α和Calponin-1的保护作用，14-3-3θ或14-3-3β过表达部分恢复了Sm22α的表达。这些结果表明，PGI2通过PPARα上调14-3-3β和14-3-3θ来保护VSMC。14-3-3β上调可抵抗细胞凋亡，而14-3-3θ和β上调可保护SM22α和Calponin-1不被降解。
We hypothesized that prostacyclin (PGI2) protects vascular smooth muscle cell (VSMC) against apoptosis and phenotypic switch through peroxisome proliferator-activated receptor-α (PPARα) activation and 14-3-3 upregulation. Here we showed that transfection of rat aortic VSMC, A-10, with PGI2-producing vectors, Ad-COPI, resulted in attenuated H2O2-induced apoptosis accompanied by a selective increase in 14-3-3β and 14-3-3θ expression. Carbaprostacyclin (cPGI2) and Wy14,643 exerted a similar effect. The effects of PGI2 were abrogated by MK886, a PPARα antagonist, but not GSK3787, a PPARδ antagonist. PPARα transfection upregulated 14-3-3β and θ expression and attenuated H2O2-induced apoptosis. H2O2-induced 14-3-3β but not 14-3-3θ degradation was blocked by a caspase 3 inhibitor. Furthermore, 14-3-3β but not 14-3-3θ overexpression reduced, while 14-3-3β siRNA aggravated apoptosis. VSMC contractile proteins and serum response factor (SRF) were reduced in H2O2-treated A-10 cells which were concurrently prevented by caspase 3 inhibitor. By contrast, PGI2 prevented H2O2-induced SM22α and Calponin-1 degradation without influencing SRF. cPGI2 and Wy14,643 also effectively blocked VSMC phenotypic switch induced by growth factors (GFs). GFs suppressed 14-3-3β, θ, ε and η isoforms and cPGI2 prevented the decline of β, θ and η, but not ε. 14-3-3θ siRNA abrogated the protective effect of cPGI2 on SM22α and Calponin-1 while 14-3-3 θ or 14-3-3β overexpression partially restored SM22α. These results indicated that PGI2 protects VSMCs via PPARα by upregulating 14-3-3β and 14-3-3θ. 14-3-3β upregulation confers resistance to apoptosis whereas 14-3-3θ and β upregulation protects SM22α and Calponin-1 from degradation.
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影响因子：
20.1
作者：
Tsai MC;Chen L;Zhou J;Tang Z;Hsu TF;Wang Y;Shih YT;Peng HH;Wang N;Guan Y;Chien S;Chiu JJ
通讯作者：
Chiu JJ
影响因子：
20.1
作者：
Feil, S;Hofmann, F;Feil, R
通讯作者：
Feil, R
DOI：
10.1073/pnas.1233635100
发表时间：
2003-08-05
影响因子：
11.1
作者：
Li, SJ;Wang, DZ;Olson, EN
通讯作者：
Olson, EN
DOI：
10.1161/01.atv.0000223875.14120.93
发表时间：
2006-07-01
影响因子：
8.7
作者：
Liou, Jun-Yang;Lee, Sang;Wu, Kenneth K.
通讯作者：
Wu, Kenneth K.
影响因子：
4.8
作者：
Nishida, W;Nakamura, M;Sobue, K
通讯作者：
Sobue, K