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Macrophages regulate plaque progression in diabetic Apoe-/- mice dependent on Pi4p/Nlrp3 signaling pathway

Wang-Xin Liu1, Yi-Fan Hu1, Guang-Jie Tai1

  • 1Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

Atherosclerosis
|September 2, 2024
PubMed
Abstract

Insights

Diabetes exacerbates atherosclerosis by affecting macrophages and inflammasomes. Targeting phosphatidylinositol 4-phosphate (PI4P) and NOD-like receptor 3 (NLRP3) in macrophages may offer new treatments for diabetic atherosclerosis.

Area of Science:

  • Cardiovascular Research
  • Immunology
  • Metabolic Diseases

Background:

  • Diabetic cardiovascular disease is a leading cause of mortality, linked to macrophages and inflammasomes.
  • NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation correlates with phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi.
  • The precise roles of PI4P and NLRP3 in macrophage function and diabetic atherosclerotic plaques remain unclear.

Purpose of the Study:

  • To investigate the expression of PI4P and NLRP3-related proteins in diabetic atherosclerosis.
  • To determine the impact of PI4P metabolic enzymes on macrophage function.
  • To evaluate the therapeutic potential of targeting PI4P and macrophages in diabetic atherosclerosis.

Main Methods:

  • Examined PI4P and NLRP3-inflammasome protein expression in apolipoprotein E-deficient (Apoe-/-) and diabetic Apoe-/- mice.
  • Manipulated PI4P levels using shRNA-Pi4kb or cDNA-Sac1 to assess effects on macrophage function.
  • Transplanted genetically modified macrophages into diabetic Apoe-/- mice to study atherosclerosis development.

Main Results:

  • Diabetes accelerated plaque progression and increased PI4P and NLRP3 expression in atherosclerotic plaques.
  • High glucose-impaired macrophage function was restored by shRNA-Pi4kb or cDNA-Sac1 transfection.
  • Reduced PI4P levels significantly decreased plaque area in diabetic Apoe-/- mice.

Conclusions:

  • PI4P and NLRP3 within macrophages significantly contribute to atherosclerosis exacerbation in diabetes.
  • PI4P metabolic enzymes (PI4KB and SAC1) represent potential therapeutic targets for diabetic atherosclerosis.
  • Macrophage-based therapies show promise for treating diabetic atherosclerosis.
Keywords:
Adoptive transferAtherosclerosisDiabetes mellitusMacrophageNlrp3Pi4p

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