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Genetic deficiency of Phactr1 promotes atherosclerosis development via facilitating M1 macrophage polarization and

Te Li1, Lijuan Ding2, Yonggang Wang3

  • 1Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

Clinical Science (London, England : 1979)
|August 29, 2020
PubMed

Insights

Phosphatase and actin regulator-1 (Phactr1) protects against atherosclerosis. Higher Phactr1 levels in monocytes indicate vulnerable plaques, while its presence reduces disease severity by activating CREB signaling and promoting M2 macrophage differentiation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Immunology

Background:

  • Genetic variants in phosphatase and actin regulator-1 (Phactr1) are linked to arteriosclerotic cardiovascular disease (ASCVD).
  • The precise role of Phactr1 in the development of atherosclerosis is not fully understood.

Purpose of the Study:

  • To investigate the function of Phactr1 in atherosclerosis.
  • To determine if Phactr1 expression in monocytes can serve as a biomarker for plaque vulnerability.
  • To elucidate the molecular mechanisms by which Phactr1 influences atherosclerotic plaque development.

Main Methods:

  • Analysis of Phactr1 expression in monocytes from patients with acute coronary syndrome (ACS) and controls.
  • Utilized Phactr1 knockout and Apoe knockout mouse models to study atherosclerosis.
  • Investigated the effect of Phactr1 deficiency on macrophage differentiation and foam cell formation.
  • Examined the role of Phactr1 in CREB signaling and KLF4 expression.

Main Results:

  • Elevated Phactr1 expression was observed in monocytes of ACS patients, particularly those with vulnerable plaques (thin-cap fibroatheroma, large lipid area).
  • Phactr1 deficiency in mice exacerbated atherosclerosis, increased macrophage infiltration, and elevated pro-inflammatory cytokines.
  • Phactr1-deficient macrophages showed a propensity for M1 polarization, increased proatherogenic cytokine production, and enhanced foam cell formation.
  • Phactr1 directly binds to CREB, promoting its phosphorylation and upregulating KLF4 expression, which partially rescues inflammation and foam cell formation.

Conclusions:

  • Increased Phactr1 in monocytes is a potential biomarker for vulnerable atherosclerotic plaques.
  • Phactr1 plays a protective role in atherosclerosis by promoting M2 macrophage differentiation and M2 polarization via CREB-mediated KLF4 induction.
  • Targeting Phactr1 may offer a therapeutic strategy for mitigating atherosclerotic cardiovascular disease.

Keywords:
CREB signalingPhactr1acute coronary syndromefoam cellmacrophage polarization

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