Role of GADD153 (growth arrest- and DNA damage-inducible gene 153) in vascular smooth muscle cell apoptosis

GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells. but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to ge notoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also report ed that GADD153 is directly associated with apoptosis, Recently we have rep orted that platelet-derived growth factor (PDGF)-BB induces apoptosis in cu ltured vascular smooth muscle cells (VSMC), but only when 100% confluency i s reached. These results suggested that cell-cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study. we explored the role of GADD153, one of a nu mber of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptos is. after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VS MC significantly reduced cell viability and induced apoptosis. In the carot id artery balloon injury model in rats, GADD153 protein was expressed in ap optotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanis ms of VSMC apoptosis.