Key result
Myeloid-specific Pim1 deficiency reduced aortic sinus atherosclerotic plaque formation by 69.4% (p=0.0185) and macrophage CD36 expression by up to 96.7% in hyperlipidemic Apoe−/− mice.
Why the study?
Does genetic deletion or pharmacological inhibition of macrophage PIM1 reduce CD36-mediated foam cell formation and atherosclerotic plaque progression in hyperlipidemic mice?
Does genetic deletion or pharmacological inhibition of macrophage PIM1 reduce CD36-mediated foam cell formation and atherosclerotic plaque progression in hyperlipidemic mice?
Answers are grounded in this paper and cite their sources.
Preclinical evidence identifies macrophage PIM1 kinase as an upstream activator of the PPARγ-CD36 lipid-uptake axis and a potential therapeutic target to inhibit foam cell formation and atherosclerotic plaque progression.
BACKGROUND: Atherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Macrophages (Mφs) significantly contribute to this process through their scavenger receptor CD36. PIM1 is a serine/threonine kinase known to modulate immune responses and cell metabolism. However, its role in Mφ lipid handling and atherogenesis is not well defined. This study examines the role of PIM1 in regulating CD36 expression and function in Mφs during foam cell formation and atherosclerosis progression. METHODS: We performed in vitro studies by treating murine peritoneal Mφs from Pim1 −/− and wild-type mice with oxLDL (oxidized low-density lipoprotein). We measured CD36, PIM1, and plaque-associated proteins and mRNA levels, oxLDL binding and uptake rates, and foam cell formation. For in vivo studies, we fed myeloid-specific Pim1 -deficient ( Apoe −/− Lyz2 Cre/+ Pim1 fl/fl ) and their littermate control ( Apoe −/− Pim1 fl/fl ) mice a high-fat diet for 12 weeks. We then evaluated plaque formation in their aortic sinuses and arches. RESULTS: Deletion of Pim1 in Mφs reduced CD36 protein expression by up to 96.7% compared with wild-type controls. This led to a 49.6% decrease in foam cell formation and a 25.5% reduction in cellular cholesterol after oxLDL treatment. Pharmacological inhibition of PIM kinase activity in wild-type Mφs also impaired oxLDL handling, with a 64.5% reduction in binding and a 57.9% reduction in uptake. Bulk RNA-sequencing revealed that Pim1 deficiency downregulated PPARγ (peroxisome proliferator-activated receptor gamma) signaling. Treatment with a PPARγ agonist restored CD36 levels in the Pim1 knockdown Mφs, suggesting that PIM1 regulates CD36 through PPARγ. Moreover, Pim1 myeloid–specific deficiency caused a 69.4% reduction in atherosclerotic plaque formation. CONCLUSIONS: PIM1 acts as a key upstream regulator of CD36 by enhancing PPARγ activity in Mφs. The PIM1-CD36 axis promotes oxLDL binding, uptake, and foam cell formation. Targeting the PIM1/PPARγ/CD36 pathway could offer new ways to modulate Mφ lipid metabolism and reduce atherosclerotic plaque progression.
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Beg et al. (2026) studied Atherosclerosis. Myeloid-specific Pim1 deficiency (Apoe−/− Lyz2Cre/+ Pim1fl/fl), whole-body Pim1 knockout (Pim1−/−), or pharmacological PIM kinase inhibition (AZD1208) vs. Littermate control mice (Apoe−/− Pim1fl/fl), wild-type macrophages, or vehicle control was evaluated on Atherosclerotic plaque cross-sectional area at the aortic sinus after 12 weeks of high-fat diet (69.4% reduction, p=0.0185). Myeloid-specific Pim1 deficiency reduced aortic sinus atherosclerotic plaque formation by 69.4% (p=0.0185) and macrophage CD36 expression by up to 96.7% in hyperlipidemic Apoe−/− mice.
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