Arteriosclerosis, thrombosis, and vascular biology · 2026
Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36.
СтатьяНазвание и аннотация: Перевод в очереди
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Beg Mirza Ahmar, Luu Quoc Quang, Chen Vaya, Wang Yaxin, Xin Gang, Cui Weiguo, Silverstein Roy L, Chen Yiliang
Аннотация
BACKGROUND: Atherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Mφs (macrophages) significantly contribute to this process through their scavenger receptor CD36 (cluster of differentiation 36). PIM1 (proviral integration site for Moloney murine leukemia virus 1) 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-/-Lyz2Cre/+Pim1fl/fl) and their littermate control (Apoe-/-Pim1fl/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.
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-/-Lyz2Cre/+Pim1fl/fl) and their littermate control (Apoe-/-Pim1fl/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.