Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Metabolism

Background:

• Atherosclerosis involves macrophage (Mφ) scavenger receptor CD36 in lipid plaque buildup.
• PIM1 kinase's role in Mφ lipid handling and atherogenesis is unclear.
• This study investigates PIM1's regulation of CD36 in Mφs during foam cell formation and atherosclerosis.

Purpose of the Study:

• To determine the role of PIM1 in regulating CD36 expression and function in macrophages.
• To examine PIM1's impact on foam cell formation and atherosclerotic plaque progression.
• To elucidate the PIM1-CD36 signaling axis in macrophage lipid metabolism.

Main Methods:

• In vitro studies using Pim1 knockout and wild-type mouse macrophages treated with oxidized low-density lipoprotein (oxLDL).
• In vivo studies using myeloid-specific Pim1-deficient and control mice fed a high-fat diet.
• Analysis of CD36, PIM1, PPARγ, oxLDL uptake, foam cell formation, and atherosclerotic plaque size.

Main Results:

• Pim1 deletion in Mφs significantly reduced CD36 expression, oxLDL uptake, and foam cell formation.
• Pharmacological PIM1 inhibition impaired oxLDL handling and reduced cellular cholesterol.
• Pim1 deficiency downregulated PPARγ signaling, and PPARγ agonism restored CD36 levels.
• Myeloid-specific Pim1 deficiency markedly reduced atherosclerotic plaque formation.

Conclusions:

• PIM1 is a key regulator of CD36 expression in Mφs via enhancing PPARγ activity.
• The PIM1-CD36 pathway promotes oxLDL uptake and foam cell formation, driving atherosclerosis.
• Targeting the PIM1/PPARγ/CD36 pathway presents a novel therapeutic strategy for atherosclerosis.