Interplay Between Heme Oxygenase-1 and the Multifunctional Transcription Factor Yin Yang 1 in the Inhibition of Intimal Hyperplasia

Abstract

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...

Repression of PDGF-R-α after cellular injury involves TNF-α, formation of a c-Fos-YY1 complex, and negative regulation by HDAC

“…c-Fos is expressed during wound repair (27) and is a prototypic member of the AP-1 transcription factor family (19,32,33) which play an important role in wound healing (3). YY1 is an injury-inducible GLI-Krüppel zinc finger protein (6,30,31). This study is the first to identify functional c-Fos and YY1 binding elements in the PDGF-R-␣ promoter.…”

Low-molecular-weight fucoidan protects endothelial function and ameliorates basal hypertension in diabetic Goto-Kakizaki rats

“…20,21 We evaluated in vivo effects of LMWF on blood pressure and local blood flow, ex vivo effects on endothelium-dependent vasodilation and eNOS expression, and in vitro effects of LMWF on eNOS phosphorylation in endothelial cells, and compared them with the effects of probucol, a lipidmodifying drug with powerful antioxidant and antiinflammatory properties used for prevention of type 2 diabetes mellitus. [22][23][24] We found that LMWF profoundly protects endothelial function against the complications of diabetes.…”

New Insights into Intracellular Locations and Functions of Heme Oxygenase-1

“…HMOX1 and CO can induce the transcription factor Yin Yang 1 (YY1) (9) that suppresses SMC proliferation without affecting EC proliferation (138). Up-regulation of YY1 by the HMOX1 inducer probucol was necessary for the inhibition of intimal hyperplasia in a rat model (9). Moreover, overexpression of YY1 can up-regulate HMOX1 expression (9).…”

“…For example, hypoxia increases HMOX1 expression in human dermal fibroblasts (127), while hypoxia is associated with decreased HMOX1 expression in human coronary artery EC, human umbilical vein EC, and immortalized human microvascular EC (88,106,119). The findings in human tissues are reminiscent of the tissue-specific effects of HMOX1 induction on cell proliferation, for example, inhibition in SMC (9,42) and stimulation in EC growth (36). By contrast, in rodents, hypoxia increases HMOX1 expression in rat pulmonary aortic EC (83), immortalized mouse EC (55), and rat aortic SMC (92).…”

“…Up-regulation of YY1 by the HMOX1 inducer probucol was necessary for the inhibition of intimal hyperplasia in a rat model (9). Moreover, overexpression of YY1 can up-regulate HMOX1 expression (9). Similarly, both vascular endothelial growth factor (VEGF) and the pro-angiogenic chemokine stromal cell-derived factor-1 (SDF-1) can induce HMOX1 or, in turn, be induced by HMOX1 (37,99).…”