MKP1, VSMC, and Vascular Remodeling

摘要 来自先前研究的压倒性证据表明，血管平滑肌细胞 (VSMCs)在新生内膜增生和动脉粥样硬化的发生发展中起关键作用，但 确切的分子机制还知之甚少。我们已经获得了令人振奋的初步数据 提示丝裂原活化蛋白激酶磷酸酶-1(MKP-1)表达下调 蛋白水平与慢性阻塞性肺疾病患者细胞增殖和狭窄程度增加有关 动脉硬化。同样，MKP-1蛋白水平和新生内膜增生减少。 钢丝介导的小鼠颈动脉损伤模型。已知MKP-1抑制细胞外信号转导通路的激活 信号转导和转录激活因子(STAT1)信号传递，这是导致 VSMC增殖和新生内膜增生。更重要的是，MKP-1的过度表达 与人主动脉平滑肌细胞(HASMC)增殖减少有关，STAT1 磷酸化，以及血管损伤后新生内膜增生的形成。使用一个 随之而来的MKP-1表达、肝细胞激酶(LKB)1活性和LKB1活性的降低 钢丝介导的颈动脉损伤后，Ser428的磷酸化水平降低。此外， LKB1在无细胞系统中直接磷酸化MKP-1，并结构性地过度表达 LKB1缺陷的A549细胞中激活的LKB1抑制MKP-1的降解。最后，特定于VSMC LKB1缺失的小鼠显示出较低水平的MKP-1在小鼠主动脉中的表达，并加剧了新生内膜 增生和动脉粥样硬化。因此，我们假设LKB1调节的MKP-1 抑制VSMC的增殖、迁移、新生内膜形成和动脉粥样硬化 通过抑制STAT1信号转导。本申请的目标是 鉴定LKB1通过MKP-1抑制VSMC增殖、内膜的机制 增殖，动脉粥样硬化，并确定MKP-1的作用是否通过 STAT1信号的抑制，已被证明促进VSMC的增殖和 内膜增生(1例)，不利于血栓消退(2例)和伤口愈合(3例)。定义 LKB1在调节VSMC增殖、内膜增生和动脉粥样硬化中的作用 可能确定治疗动脉粥样硬化性血栓性血管疾病的潜在靶点。

Abstract Overwhelming evidence from previous studies suggests that vascular smooth muscle cells (VSMCs) plays a critical role in development of neointima hyperplasia and atherosclerosis but exact molecular mechanisms are poorly understood. We have obtained exciting preliminary data suggesting that down-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1) protein levels is associated with increased cell proliferation and stenosis in patients with atherosclerosis. Similarly, MKP-1 protein levels and neointimal hyperplasia are decreased in a mouse model of wire-mediated carotid artery injury. MKP-1 is known to suppress activation of signal transducer and activator of transcription (STAT1) signaling, a critical step leading to VSMC proliferation and neointimal hyperplasia. More importantly, MKP-1 overexpression is associated with decreased human aortic smooth muscle cell (HASMC) proliferation, STAT1 phosphorylation, and neointimal hyperplasia formation in response to vascular injury. With a concomitant reduction in MKP-1 expression, both liver kinase (LKB)1 activity and LKB1 phosphorylation at Ser428 is decreased in the carotid artery after wire-mediated injury. Further, LKB1 directly phosphorylates MKP-1 in a cell-free system, and overexpression of constitutively active LKB1 in LKB1-deficient A549 cells inhibits MKP-1 degradation. Finally, VSMC-specific LKB1 deletion mice exhibit lower levels of MKP-1 in mouse aortas and exacerbated neointimal hyperplasia and atherosclerosis. Thus we hypothesize that LKB1-regulated MKP-1 suppresses VSMC proliferation, migration, neointimal formation, and atherosclerosis through the inhibition of STAT1 signaling. The goals of the present application are to characterize the mechanism by which LKB1 via MKP-1 suppresses VSMC proliferation, intimal hyperplasia, atherosclerosis, and determine whether the effect of MKP-1 is mediated through the inhibition of STAT1 signaling, which has been shown to promote VSMC proliferation and intimal hyperplasia (1) and impair thrombus resolution (2) and wound healing (3). Defining the roles of LKB1 in the regulation of VSMC proliferation, intimal hyperplasia, and atherosclerosis may identify potential targets for the treatment of atherothrombotic vascular diseases.