Prostacyclin and PPAR? agonists control vascular smooth muscle cell apoptosis and phenotypic switch through distinct 14-3-3 isoforms.

ABSTRACT: We hypothesized that prostacyclin (PGI2) protects vascular smooth muscle cell (VSMC) against apoptosis and phenotypic switch through peroxisome proliferator-activated receptor-? (PPAR?) 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 14-3-3? and 14-3-3? expression. Carbaprostacyclin (cPGI2) and Wy14,643 exerted a similar effect. The effects of PGI2 were abrogated by MK886, a PPAR? antagonist, but not GSK3787, a PPAR? antagonist. PPAR? transfection upregulated 14-3-3? and ? expression and attenuated H2O2-induced apoptosis. H2O2-induced 14-3-3? but not 14-3-3? degradation was blocked by a caspase 3 inhibitor. Furthermore, 14-3-3? but not 14-3-3? overexpression reduced, while 14-3-3? 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 SM22? and Calponin-1 degradation without influencing SRF. cPGI2 and Wy14,643 also effectively blocked VSMC phenotypic switch induced by growth factors (GFs). GFs suppressed 14-3-3?, ?, ? and ? isoforms and cPGI2 prevented the decline of ?, ? and ?, but not ?. 14-3-3? siRNA abrogated the protective effect of cPGI2 on SM22? and Calponin-1 while 14-3-3 ? or 14-3-3? overexpression partially restored SM22?. These results indicated that PGI2 protects VSMCs via PPAR? by upregulating 14-3-3? and 14-3-3?. 14-3-3? upregulation confers resistance to apoptosis whereas 14-3-3? and ? upregulation protects SM22? and Calponin-1 from degradation.

SUBMITTER: Chen YC 

PROVIDER: S-EPMC3701049 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature