phenylhydrazonopyrazolone-sulfonate-1 and Disease-Models--Animal

To address the roles of SHP2 in regulating angiotensin II (Ang II) induced abdominal aortic aneurysm (AAA) and the potential molecular mechanisms.. AAA model was established in apolipoprotein E-deficient (apoE. Treatment with PHPS1 (SHP2 inhibitor) significantly decreased the vascular diameter of AAA. Histological analysis showed that PHPS1 obviously reduced the Masson positive area, macrophages positive area, as well as the damage rate of elastic laminae. Moreover, PHPS1 suppressed the expression of INF-γ, TNF-α and MMPs, as well as elevated IL-10 and arginase-1 expression. Additionally, PHPS1 enhanced the expression of granulocytic MDSCs (G-MDSCs). By consulting with bioinformatics, STAT3 was selected. In G-MDSCs, PHPS1 stimulation obviously increased the phosphorylation level of STAT3, as well as elevated the protein expression of C/EBPβ and arginase-1. However, the above phenomena can be blocked after Stattic (STAT3 inhibitor) treatment.. SHP2 may affect the AAA progression by interfering with expansion and function of MDSCs to regulate the body immunity, which might afford a novel direction for the treatment of patients with AAA.

Topics: Angiotensin II; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Benzenesulfonates; Disease Models, Animal; Hydrazones; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Myeloid-Derived Suppressor Cells; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction

Smooth 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.. After exposure to a high-cholesterol diet for 4 weeks, LDL receptor-deficient (Ldlr. PHPS1 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. The SHP2 inhibitor PHPS1 exerts a protective effect against atherosclerosis by reducing VSMC proliferation via SHP2/ERK pathway activation.

Topics: Animals; Aorta; Aortic Diseases; Atherosclerosis; Benzenesulfonates; Cell Proliferation; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Hydrazones; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Plaque, Atherosclerotic; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, LDL; Signal Transduction

SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergic mice. Blockade of SHP2 function by SHP2 inhibitor PHPS-1 or conditional shp2 knockdown by adenovirus-inhibited bone-marrow-derived eosinophil differentiation in vitro, with no detectable effects on the apoptosis of eosinophils. Furthermore, SHP2 induced eosinophil differentiation via regulation of the extracellular signal-regulated kinase pathway. Myeloid shp2 conditional knockout mice (LysM(cre)shp2(flox/flox)) failed to induce eosinophilia as well as airway hyper-responsiveness. The SHP2 inhibitor PHPS-1 also alleviated eosinophilic airway inflammation and airway hyper-responsiveness, accompanied by significantly reduced levels of systemic eosinophils and eosinophil lineage-committed progenitors in allergic mice. We demonstrate that inhibition of eosinophil development is SHP2-dependent and SHP2 is sufficient to promote eosinophil formation in vivo. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.

Topics: Animals; Asthma; Benzenesulfonates; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Cytokines; Disease Models, Animal; Eosinophils; Extracellular Signal-Regulated MAP Kinases; GATA1 Transcription Factor; Hydrazones; Interleukin-5; Lung; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Basic Protein; Ovalbumin; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Recombinant Proteins; Signal Transduction