Home » Key Scientific Articles » Prostacyclin and PPAR{Alpha} agonists control vascular smooth muscle cell apoptosis and phenotypic switch through distinct 14-3-3 isoforms.

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

Chen YC, Chu LY, Yang SF, Chen HL, Yet SF, Wu KK.

PLoS One. 2013 ;8(7):e69702.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan.

 

Abstract

We hypothesized that prostacyclin (PGI2) protects vascular smooth muscle cell (VSMC) against apoptosis and phenotypic switch through peroxisome proliferator-activated receptor-{Alpha} (PPAR{Alpha}) 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{Beta} and 14-3-3θ expression. Carbaprostacyclin (cPGI2) and Wy14,643 exerted a similar effect. The effects of PGI2 were abrogated by MK886, a PPAR{Alpha} antagonist, but not GSK3787, a PPAR{Delta} antagonist. PPAR{Alpha} transfection upregulated 14-3-3{Beta} and θ expression and attenuated H2O2-induced apoptosis. H2O2-induced 14-3-3{Beta} but not 14-3-3θ degradation was blocked by a caspase 3 inhibitor. Furthermore, 14-3-3{Beta} but not 14-3-3θ overexpression reduced, while 14-3-3{Beta} siRNA aggravated apoptosis. VSMC contractile proteins and serum response factor (SRF) were reduced in H2O2-treated A-10 cellswhich were concurrently prevented by caspase 3 inhibitor. By contrast, PGI2 prevented H2O2-induced SM22{Alpha} 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{Beta}, θ, ε and η isoforms and cPGI2 prevented the decline of {Beta}, θ and η, but not ε. 14-3-3θ siRNA abrogated the protective effect of cPGI2 on SM22{Alpha} and Calponin-1 while 14-3-3 θ or 14-3-3{Beta} overexpression partially restored SM22{Alpha}. These results indicated that PGI2 protects VSMCs via PPAR{Alpha} by upregulating 14-3-3{Beta} and 14-3-3θ. 14-3-3{Beta} upregulation confers resistance to apoptosis whereas 14-3-3θ and {Beta} upregulation protects SM22{Alpha} and Calponin-1 from degradation.

 

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