Wild-type p53-induced phosphatase 1 promotes vascular smooth muscle cell proliferation and neointima hyperplasia after vascular injury via p-adenosine 5′-monophosphate-activated protein kinase/mammalian target of rapamycin complex 1 pathway

Vascular restenosis badly harms the curative effect of revascularization, despite the fact that novel treatments especially percutaneous interventions of coronary, carotid and other peripheral arteries have made great progress over the past 20 years [1,2]. Therefore, revealing the underlying mechanisms and searching for novel therapeutic targets of restenosis are to be urgently solved. The initiating step of vascular restenosis is de-endothelization and compression of atherosclerotic plaque into vascular wall via mechanical injury [3]. Whereafter, activated platelet and inflammatory cells gather at damaged area and secrete several cytokines, such as platelet-derived growth factor (PDGF), interleukin-6 and interleukin-1β, and so forth [3]. These processes initiate subsequent proliferation and migration of vascular smooth muscle cells (VSMCs) and lead to neointima hyperplasia, vascular remodeling and restenosis [3]. As the major components of vascular wall, VSMCs play a crucial role in maintaining normal function of blood vessels (e.g. self-repairment) but also in neointima formation owing to the high proliferative activity [4]. Accordingly, preventing excessive VSMC proliferation is emerging as a potent method for restenosis treatment. Numerous studies have shown that, in mammalian bodies, VSMCs maintain a balance between proliferation and apoptosis. Under certain pathological conditions, VSMCs switch to a synthetic growth phenotype, which is characterized by excessive proliferation and migration [5,6]. The contractile-to-synthetic growth transition is a multifactorial process that involves many signaling pathways including cytokines, protein kinases, transcription factors and regulatory RNA molecules, and so forth. Though treatments based on aforementioned pathways, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, a classical pathway regulating VSMC proliferation [7,8], have been introduced, the morbidity of restenosis still reached 10% [2]. Therefore, unraveling the novel underlying mechanism regulating VSMC proliferation is of great significance for preventing vascular restenosis. The wild-type p53-induced phosphatase 1 (Wip1), a member of the PP2C family of Ser/Thr protein phosphatases, is also addressed as protein phosphatase magnesium-dependent 1 delta (PPM1D) [9]. Overexpressed in various tumors, Wip1 is originally emerging as an oncogene regulating tumorigenesis via its regulation of apoptosis [10,11]. At the molecular level, regulation of ATM in the mammalian target of rapamycin (mTOR) and P53 is discovered to play a key role in Wip1-mediated tumorigenesis [12]. Many studies have found that Wip1 also participates in other biological processes, such as neurogenesis [13], organismal aging [14] and haematopoietic stem cell homeostasis [15]. Wip1 is recently discovered to exert a pro-atherosclerotic role in the pathological process of atherosclerosis, during which autophagy, cholesterol efflux and macrophage migration are involved [16,17]. In the above study, adenosine 5′-monophosphate-activated protein kinase (AMPK) is also confirmed to be involved in ATM-dependent regulation of mTOR [16]. Vascular restenosis has similar pathological processes to atherosclerosis, such as VSMC proliferation and migration [18], reminding us that Wip1 may also be a potent functional regulator in vascular restenosis. However, whether Wip1 is associated with VSMC proliferation, neointima hyperplasia and restenosis after vascular injury is largely unknown. In the current study, we describe a regulatory role for Wip1 in vascular restenosis, in which AMPK/mTORC1 pathway is involved. By using a Wip1 antagonist GSK2830371 (GSK), we found that Wip1 inhibition suppresses VSMC proliferation and neointima hyperplasia, accompanied by enhanced AMPK phosphorylation and decreased mTORC1 activity. Further study shows GSK fails to prevent VSMC proliferation and neointima hyperplasia in mice with tuberous sclerosis 1 (TSC1) knockdown, and thus leading to enhanced restenosis. Our research shows that Wip1-dependent modulation of VSMC proliferation and neointima hyperplasia by means of AMPK/mTORC1 may be identified as a potential therapeutic intervention for vascular restenosis.