Abstract-Activation transcription factor (ATF)-4 is a member of the ATF/CREB family of basic leucine zipper transcription factors that regulates cellular responses to a variety of stresses. The role of ATF-4 in smooth muscle cells of the vessel wall is completely unknown. Here, we show that ATF-4 expression is induced in smooth muscle cells in response to injury, both in vitro using a model of mechanical injury and in the media of balloon-injured rat carotid arteries. We demonstrate that ATF-4 is activated by fibroblast growth factor (FGF)-2, an injury-induced mitogen, through the phosphatidylinositol 3-kinase pathway. Injury also activates vascular endothelial growth factor (VEGF) -
Objective: Because such cell-specific effects are reminiscent of the action of the transcription factor Yin Yang (YY)1, we tested the hypothesis that there is a functional relationship between HO-1 and YY1. Methods and Results: We report that probucol increases the number of YY1؉ cells in rat carotid artery following balloon injury at a time coinciding with increased HO-1 expression. The drug also induces the expression of YY1 mRNA and protein in rat aortic smooth muscle cells (RASMCs) in vitro, as do other known HO-1 inducers (tert-butylhydroquinone and hemin) and overexpression of HO-1 using a human HMOX1 cDNA plasmid. Conversely, overexpression of YY1 induces expression of HO-1 in RASMCs. Induction of YY1 expression is dependent on HO-1 enzyme activity and its reaction product CO, because pharmacological inhibition of heme oxygenase activity or CO scavenging block, whereas exposure of RASMCs to a CO-releasing molecule increases, YY1 expression. Furthermore, RNA interference knockdown of YY1 prevents probucol or adeno-HO-1 from inhibiting RASMC proliferation in vitro and neointimal formation in vivo. Key Words: Heme oxygenase-1 Ⅲ smooth muscle cell proliferation Ⅲ YY1 Ⅲ carbon monoxide Ⅲ probucol A therosclerotic vascular disease is the leading cause of mortality in the Western world. Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in atherogenesis and restenosis after angioplasty or stenting. 1 Agents that inhibit the proliferation of VSMCs are of considerable therapeutic importance for the treatment of cardiovascular diseases. This is particularly the case for in-stent restenosis, the incidence of which has been reduced dramatically by the widespread use of stents that elute cell proliferation-inhibitory drugs. However, the incidence of in-stent thrombosis remains a significant clinical problem 2 given the potentially life threatening consequences of a thrombotic event. The endothelium plays a crucial role in the prevention of in-stent thrombosis, with delayed reendothelialization likely responsible for late stent thrombosis. 3 Most conventional, orally administered, drugs have failed to inhibit restenosis in humans following coronary angioplasty and stenting, 4 -6 one exception being probucol, a rarely used lipid-lowering drug with antiinflammatory and antioxidant properties. 7 Probucol has also been reported to inhibit experimental in-stent thrombosis. 8 These beneficial effects are associated with promotion of endothelial cell growth and enhancement of reendothelialization and inhibition of VSMC proliferation. 9 Recent evidence suggests that the mechanisms of probucol and related compounds to inhibit VSMC proliferation, as well as experimental restenosis and atherosclerosis, are mediated via induction of the enzyme heme oxygenase (HO)-1. 10,11 HO-1 is the inducible of 2 forms of heme oxygenases that degrade heme to CO, Fe 2ϩ , and biliverdin, which is then The HO-1-induced opposing effect on the growth of VSMCs versus endothelial cells is reminiscent of the effect...
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