SHP2 inhibitor PHPS1 protects against atherosclerosis by inhibiting smooth muscle cell proliferation

Abstract

BackgroundSmooth muscle cells play an important role in the development of atherosclerosis. SHP2 is known to regulate the proliferation and migration of smooth muscle cells. The purpose of this study was to determine whether the SHP2 inhibitor PHPS1 has a pro-atherosclerotic or an atheroprotective effect in vivo and in vitro.MethodsAfter exposure to a high-cholesterol diet for 4 weeks, LDL receptor-deficient (Ldlr−/−) mice were exposed to the SHP2 inhibitor PHPS1 or vehicle. Body weight, serum glucose and lipid levels were determined. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining and immunohistochemistry. The phosphorylation of SHP2 and related signaling molecules was analyzed by Western blot. Mechanistic analyses were performed in oxLDL-stimulated cultured vascular smooth muscle cells (VSMCs) with or without 10 mM PHPS1 pretreatment. Protein phosphorylation levels were detected by Western blot, and VSMC proliferation was assessed by BrdU staining.ResultsPHPS1 decreased the number of atherosclerotic plaques without significantly affecting body weight, serum glucose levels or lipid metabolism. Plaque composition analysis showed a significant decrease in the number of VSMCs in atherosclerotic lesions of Ldlr−/− mice treated with PHPS1. Stimulation with oxLDL induced a dose-dependent increase in the number of VSMCs and in SHP2 and ERK phosphorylation levels, and these effects were blocked by PHPS1.ConclusionThe SHP2 inhibitor PHPS1 exerts a protective effect against atherosclerosis by reducing VSMC proliferation via SHP2/ERK pathway activation.Electronic supplementary materialThe online version of this article (10.1186/s12872-018-0816-2) contains supplementary material, which is available to authorized users.

Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling

“…In line with this, a recent study also showed that PTP1B deletion in ApoE −/− /LysM-PTP1B mice could reduce the size of atherosclerotic plaque [67]. Likewise, SHP2 has been identified as a drug target for acute myeloid leukemia [68,69] solid tumors [70], and atherosclerosis by negatively regulating smooth muscle cell proliferation [71]. We thereby hypothesize that nanotopography may synergize with the pharmacological inhibition of a specific target to promote desirable EC behaviors amenable to endothelialization.…”

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model

“…We recently reported that SHP1, but not SHP2, reduces PD-L1-dependent regulation of T regulatory lymphocyte (Treg) function and is associated with resolution of shock- and sepsis-induced lung injury (Tang et al 2015 ). Additionally, previous research has demonstrated that SHP2 deficiency may have a protective effect in experimental renal (Hsu et al 2017 ; Teng et al 2018 ; Verma et al 2016 ) and cardiovascular (Chen et al 2018 ) injury. Thus, it appears that SHP2 activation may have differential effects depending on the location of action.…”

SHP2 inhibitor PHPS1 ameliorates acute kidney injury by Erk1/2-STAT3 signaling in a combined murine hemorrhage followed by septic challenge model.

“…We recently reported that SHP1, but not SHP2, negatively modulated PD-L1 dependent regulation of T regulatory lymphocyte (Treg) function and in so doing contributed to resolving shock/sepsis-induced lung injury (Tang et al 2015). At the same time, some studies have revealed that SHP2 de ciency may have a protective effect in experimental renal (Hsu et al 2017, Teng et al 2018, Verma et al 2016) and cardiovascular (Chen et al 2018) conditions. Thus, SHP2 activation may play distinct roles in different organs.…”