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.
The goal of this new application is to establish the essential roles of liver kinase B1 (LKB1) - mitogen-activated protein kinase phosphatase-1 (MKP1) - Signal transducer and activator of transcription 1 (STAT1) pathway in vascular remodeling including restenosis and atherosclerosis. The proposed project has the potential to establish that the LKB1- MKP-1-STAT1 regulatory axis is specific for vascular smooth muscle cells in the regulation of intimal hyperplasia and atherosclerosis.
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