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Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice
Chenxia Wu1,2, Peiyao Zheng3, Lan Ma4
1Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China (C.W., L.H.).
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 LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2:ApoE or Shp2:Ldlr mice and exo-AAV8-SHP2E76K/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 LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR 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/LDLR null mice.
Insights
Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) in macrophages acts as an antiatherosclerotic regulator. SHP2 stabilizes peroxisome proliferative activated receptor γ (PPARγ), reducing inflammation and improving efferocytosis in atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Macrophages play diverse roles in atherosclerosis development.
- Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) regulates macrophage activation, but its specific role in the atherosclerotic microenvironment is unclear.
Purpose of the Study:
- To elucidate the mechanism by which SHP2 regulates macrophage function in atherosclerosis.
- To investigate the therapeutic potential of targeting SHP2 in atherosclerosis.
Main Methods:
- Utilized apolipoprotein E (APOE) or low-density lipoprotein receptor (LDLR) null mice fed a Western diet, with SHP2 inhibition or deletion in macrophages.
- Employed in vitro studies on mouse peritoneal macrophages to assess inflammatory factors and phagocytic function.
- Conducted RNA sequencing to identify downstream targets, including peroxisome proliferative activated receptor γ (PPARγ).
Main Results:
- SHP2 inhibition or deletion aggravated atherosclerosis, increasing plaque macrophages and apoptotic cells, while impairing efferocytosis.
- SHP2 gain-of-function reduced atherosclerosis; SHP2 agonist lovastatin repressed inflammation and enhanced efferocytosis.
- SHP2 deficiency led to decreased PPARγ, which was stabilized by SHP2, and PPARγ agonists rescued atherosclerotic phenotypes.
Conclusions:
- SHP2 in macrophages acts as an antiatherosclerotic regulator by stabilizing PPARγ.
- Targeting SHP2 or its downstream pathways represents a potential therapeutic strategy for atherosclerosis.
