Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice

Abstract

Background: Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown. Methods: APOE (apolipoprotein E) or low-density lipoprotein receptor null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2 MKO :ApoE −/− or Shp2 MKO :Ldlr −/− mice and exo-AAV8-SHP2 E76K / ApoE −/− mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice. Results: Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and low-density lipoprotein receptor null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and low-density lipoprotein receptor null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels. Conclusions: Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/low-density lipoprotein receptor null mice.

Targets of tumor microenvironment for potential drug development

“…170 Presently, several inhibitors have been developed, among which JAB-3068, BBP-398, and RMC-4630 have entered clinical trials. 171 In addition, the role of SHP2 in macrophages and fibroblasts has been studied, 196,197 and it may be essential for vascular development. Lately, Xu et al demonstrated that SHP2 expression is upregulated in TECs, and it promotes angiogenesis as well as vessel defects through the SHP2-ASK1-c-Jun-SOX7 axis, which may benefit tumor growth.…”