Clarification of the role of apoptosis in the formation of vascular lesion and application of apoptosis-inducing factor to the treatment of restenosis after stent implantation.

Mst1是一种丝氨酸/苏氨酸激酶，参与细胞凋亡过程。然而，Mstl在血管中的作用至今未见报道。staturosporine刺激血管平滑肌细胞（VSMCs）诱导凋亡和Mstl的激活。大鼠颈动脉球囊损伤后，Mstl在新生内膜中的表达增加。通过腺病毒载体在损伤大鼠颈动脉中过表达Mstl，可增加TUNEL阳性细胞的数量，减少新内膜形成的程度。我们还发现肿瘤坏死因子□（TNF□）通过诱导活性氧诱导内皮细胞（ECs）中Mstl的活化。siRNA敲低Mstl表达可减弱TNF□诱导的内皮细胞凋亡。接下来，我们研究了诱导性cAMP早期抑制因子（ICER）的作用，这是一种转录抑制因子，其表达是由cAMP诱导的。Beraprost是一种PGI2衍生物，以剂量和时间依赖性的方式诱导VSMCs中ICER的表达。Beraprost抑制血小板源性生长因子诱导的VSMCs生长。通过siRNA敲低ICER表达可减弱贝拉普罗素诱导的生长抑制，这表明贝拉普罗素诱导的生长抑制至少部分是由诱导ICER介导的。腺病毒载体过表达ICER诱导大鼠颈动脉球囊损伤后VSMCs凋亡，抑制新内膜形成。这些结果表明，可能通过调节Mstl或ICER的表达和/或活性来抑制VSMCs的生长。这些分子可应用于动脉粥样硬化和支架内再狭窄等血管疾病的治疗。

Mst1 is a serine/threonine kinase that is involved in the process of apoptosis. However, the role of Mstl in the blood vessel has not been reported to date. Stimulation of vascular smooth muscle cells (VSMCs) with staturosporine induced apoptosis as well as activation of Mstl. After balloon injury of rat carotid artery, the expression of Mstl was increased in the neointima. Overexpression of Mstl by an adenovirus vector in the injured rat carotid artery enhanced the number of TUNEL positive cells and reduced the extent of neointimal formation. We also found that tumor necrosis factor □ (TNF□) induced activation of Mstl in endothelial cells (ECs) through induction of reactive oxygen species. Knockdown of the Mstl expression by siRNA attenuated TNF□ -induced apoptosis of ECs.We next examined the role of inducible cAMP early repressor (ICER), a transcription repressor, of which expression is induced by cAMP. Beraprost, a PGI2 derivative, induced the expression of ICER in VSMCs in a dose-and time-dependent manner. Beraprost inhibited platelet-derived growth factor-induced growth of VSMCs. Knockdown of ICER expression by siRNA attenuated the beraprost-induced growth suppression, suggesting that beraprost-induced growth suppression is, at least in part, mediated by induction of ICER. Overexpression of ICER by an adenovirus vector induced the apoptosis of VSMCs and inhibited neointimal formation after balloon injury of rat carotid artery.These results suggest that it may be possible to inhibit growth of VSMCs by modulating the expression and/or activity of Mstl or ICER. These molcules may be applied to the treatment of vascular diseases such as atherosclerosis and in-stent restenosis.