Biology subjects

Silverstein, R. L.

Publications and source records attributed to Silverstein, R. L..

3 recordsLinked to original sources

bioRxiv2025

Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36

BackgroundAtherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Macrophages (M{varphi}s) 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 M{varphi} lipid handling and atherogenesis is not well defined. This study examines the role of PIM1 in regulating CD36 expression and function in M{varphi}s during foam cell formation and atherosclerosis progression. MethodsWe performed in vitro studies by treating murine peritoneal M{varphi}s from Pim1-/- and wild-type (WT) mice with oxidized low-density lipoprotein (oxLDL). We measured CD36, PIM1, and plaque-associated proteins and mRNA levels, oxLDL binding and uptake rates, as well as foam cell formation. For in vivo studies, we fed M{varphi}-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 the plaque formation in their aortic sinuses and arches. ResultsDeletion of Pim1 in M{varphi}s reduced CD36 protein expression by up to 96.7% compared to WT 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 WT M{varphi}s also impaired oxLDL handling, with a 64.5% reduction in binding and a 57.9% in uptake. Bulk RNA-seq revealed that Pim1 deficiency downregulated PPAR{gamma} signaling. Treatment with a PPAR{gamma} agonist restored CD36 levels in the PIM1 knockdown M{varphi}s, suggesting that PIM1 regulates CD36 through PPAR{gamma}. Moreover, PIM1 M{varphi}-specific deficiency caused a 69.4% reduction in atherosclerotic plaque formation. ConclusionPIM1 acts as a key upstream regulator of CD36 by enhancing PPAR{gamma} activity in M{varphi}s. The PIM1-CD36 axis promotes oxLDL binding, uptake, and foam cell formation. Targeting the PIM1/PPAR{gamma}/CD36 pathway could offer new ways to modulate M{varphi} lipid metabolism and reduce atherosclerotic plaque progression. Non-standard Abbreviations and AcronymsELISA: enzyme-linked immunosorbent assay; HFD: high-fat diet; M{varphi}s: macrophages; MCP-1: monocyte chemoattractant protein-1; ORO: oil red O; oxLDL: oxidized low-density lipoprotein; PBS: phosphate-buffered saline; PPAR{gamma}: peroxisome proliferator-activated receptor gamma; WT: wild type.

immunology↗

bioRxiv2025

Na/K-ATPase Signaling in Adipocytes Promotes Atherosclerosis

BACKGROUNDAdipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified Na/K-ATPase (NKA) 1 as a signal transducer that activates Src family kinases and promotes oxidative stress and inflammation in various cell types, including adipocytes and macrophages. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. Here, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis. METHODSAdipocyte-specific NaKtide (Adipo-NaKtide) was delivered to Apoe-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western Diet (WD) for 12 weeks to induce atherosclerosis and then assessed for atherosclerotic plaque burden the aortic arch and at the level of the aortic sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma. RESULTSAdipo-NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and 47% in the aortic sinus. CD68+ macrophage and -SMA+ smooth muscle cell content in the aortic sinus were decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and lowered systemic inflammation. CONCLUSIONSThese findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis, suggesting an important endocrine and/or paracrine influence of adipose tissue on large artery atherogenesis, and supporting the therapeutic potential of targeting NKA in cardiometabolic disease.

molecular biology↗

bioRxiv2020

LPA/PKD-1 signaling promotes development of arteriolar niche that supports self-renewal of breast cancer stem cells and stemness

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. However, the regulatory mechanisms of self-renewal and interactions with the vascular niche within tumor microenvironment are currently under investigation. Here, we demonstrate that BCSCs are enriched within arteriolar niche within the tumor microenvironment of estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the LPA/PKD-1 signaling pathway, which promotes arteriolar differentiation and self-renewal. Furthermore, this pathway directly promotes stemness features. These findings suggest that targeting LPA/PKD-1 signaling may disrupt the arteriolar niche within the tumor microenvironment and concomitantly eradicate BCSCs, thereby attenuating BC progression.

cancer biology↗