Abstract
Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-β (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.
Highlights
Our results showed that PDGFPGK1 and HIF-1α proteins
Transient arterial occlusion induced by catheter balloon inflation creates a hypoxic model
Transient arterial occlusion induced by catheter balloon inflation creates a hypoxic condition,which which might upregulate
Summary
Suppressing local expression of HIF-1 can effectively reinduced to play a critical role inneointima regulatingformation cell survival, was thushypoxia involvedplays in restenosis duce arterial injury-induced [9], and suggesting a role in progression [7,8,9]. PDGF and VEGF have been demonstrated as restenosis-promoting growth factors that can unclear there areof interactions that exist and PGK1 under facilitate whether the development restenosis [18,19] Toamong date, it PDGF, remainsVEGF, unclear whether there hypoxic condition. VSMC proliferation and migration, to clarify inflation-injured arterial walls during neointimal formation, to investigate the pathological the of effects growth factors on PGK1 expression.
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