Biology subjects

Opoku, E.

Publications and source records attributed to Opoku, E..

6 recordsLinked to original sources

bioRxiv2026

Myeloid-Specific Pck1 Deficiency Does Not Alter Aortic Root Atherosclerosis in Mice

BackgroundWe previously performed a strain intercross between atherosclerosis resistant AKR Apoe-/-mice and atherosclerosis sensitive DBA/2 Apoe-/- mice and identified the Ath28 quantitative trait locus (QTL) on the distal end of chromosome 2. Congenic strain fine mapping identified the Ath28.1 QTL atherosclerosis modifying subregion, encompassing 217 Kb, containing for only three protein-coding genes, Zbp1, Pck1, and Pmepa1, encoding respectively, Z-DNA binding protein 1, phosphoenolpyruvate carboxykinase 1, and prostate transmembrane protein androgen induced 1. MethodsThe effect of macrophage-specific knockout of Pck1 (KO) was tested using the AAV2 transduced proprotein convertase subtilisin kexin type 9 (PCSK9) overexpression mouse model of hyperlipidemia and atherosclerosis. ResultsUnexpectedly, macrophage Pck1 deficiency lowered body weight, liver weight, and HDL-cholesterol levels in both sexes, while total and non-HDL cholesterol levels were only decreased in male mice. Aortic root lesion area and necrotic lesion area were unchanged in KO mice of both sexes. ConclusionPck1 was not confirmed as an atherosclerosis modifier gene.

genetics↗

bioRxiv2023

Disulfiram reduces atherosclerosis and enhances efferocytosis, autophagy, and atheroprotective gut microbiota in hyperlipidemic mice.

Pyroptosis executor Gasdermin (GsdmD) promotes atherosclerosis in mice and humans. Disulfiram (DSF) was recently shown to potently inhibit GsdmD, but the in-vivo efficacy and mechanism of DSFs anti-atherosclerotic activity is yet to be explored. We used human/mouse macrophages and a hyperlipidemic mouse model of atherosclerosis to determine DSF anti-atherosclerotic efficacy and mechanism. DSF-fed hyperlipidemic apoE-/- mice showed significantly reduced IL-1{beta} release upon in-vivo Nlrp3 inflammasome assembly and showed smaller atherosclerotic lesions ([~]27% and 29% reduction in males and females, respectively). The necrotic core area was also smaller ([~]50% and 46% reduction in DSF-fed males and females, respectively). DSF induced autophagy in macrophages, hepatocytes/liver, and in atherosclerotic plaques. DSF modulated other atheroprotective pathways such as efferocytosis, phagocytosis, and gut microbiota. DSF-treated macrophages showed enhanced phagocytosis/efferocytosis, with a mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic-force microscopy analysis revealed altered biophysical membrane properties of DSF treated macrophages, showing increased ordered-state of the plasma membrane and increased adhesion strength. Furthermore, the 16sRNA sequencing of DSF-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species. Taken together, our data shows that DSF can simultaneously modulate multiple atheroprotective pathways, and thus may serve as novel adjuvant therapeutic to treat atherosclerosis.

cell biology↗

bioRxiv2022

Miltefosine attenuates inflammation, reduces atherosclerosis, and alters gut microbiota in hyperlipidemic mice.

Excess cholesterol induces foam cell formation, NLRP3 inflammasome activation, and IL-1{beta} release in atherosclerotic plaques. We have shown previously that Miltefosine increased cholesterol release and dampened NLRP3 inflammasome assembly in macrophages. Here, we show that Miltefosine reduced LPS-induced choline uptake by macrophages and attenuated NLRP3 inflammasome assembly in mice. Miltefosine-fed mice showed reduced plasma IL-1{beta} in a polymicrobial cecal slurry injection model of systemic inflammation. Miltefosine-fed mice showed increased reverse cholesterol transport from macrophages to plasma, liver, and feces. Hyperlipidemic apoE-/- mice fed with Miltefosine showed significantly reduced weight gain and markedly reduced atherosclerotic lesions vs. control mice. 16S rDNA sequencing and analysis showed alterations in the gut microbiota profile of Miltefosine-fed hyperlipidemic apoE-/- vs. control mice, with the most notable changes in Romboutsia and Bacteroidetes species. Taken together, these data indicate that Miltefosine causes pleiotropic effects on lipid metabolism, inflammasome activity, atherosclerosis, and the gut microbiota.

cell biology↗

bioRxiv2022

Myeloid-cell-specific role of Gasdermin D in promoting lung cancer progression in mice.

The activities of the NLRP3 and AIM2 inflammasomes and Gasdermin D (GsdmD), the final executor of inflammasome activity, are implicated in lung cancer pathophysiology but its not clear if their contributions promote or retard lung cancer progression. GsdmD plays a role in release of interleukin-1beta (IL-1 {beta}), and the CANTOS trial and recent studies have highlighted a crucial role of IL-1{beta} in promoting lung cancer. Expression of GsdmD was shown to be upregulated in human non-small cell lung cancer (NSCLC) tissue, but its contribution to in vivo lung cancer metastasis is not known. Using a metastatic Lewis Lung Carcinoma (LLC) cell model, we show that GsdmD knockout (GsdmD-/-) mice form significantly fewer cancer foci in lung, and exhibit markedly decreased lung cancer metastasis. Furthermore, GsdmD-/- mice show a significant ~ 50% increase in median survival rate vs. isogenic WT C57BL6J mice. The cleaved forms of GsdmD and IL-1 {beta} were detected in lung tumor tissue, indicating inflammasome activity in lung tumor microenvironment (TME). Increased migration and growth of LLC cells was observed upon exposure to the conditioned media derived from inflammasome-induced wild type, but not the GsdmD-/-, macrophages. Exposure of human A549 lung cancer cells to the conditioned media derived from inflammasome-induced THP-1 macrophages also resulted in increased cell migration. Using bone marrow transplantation, we show the myeloid-specific contribution of GsdmD in lung cancer metastasis. Taken together, our data show that inflammasome activation in macrophages promotes lung cancer growth and migration, and GsdmD plays a myeloid-specific role in lung cancer progression in mice.

cancer biology↗

bioRxiv2021

Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis.

Activation of inflammasomes, such as Nlrp3 and Aim2, can exacerbate atherosclerosis in mice and humans. Gasdermin D (GsdmD) serves as a final executor of inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-1{beta}). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1{beta} antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/AIM2 and IL-1{beta} nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet fully clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1{beta} vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1{beta} dependent fashion. The GsdmD-/- mice were resistant to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed the role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing sections stained positive for the cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD in atherosclerotic plaques. Our data show that GsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis. SummaryGsdmD mediates inflammation-induced defects in RCT and promotes atherosclerosis.

pathology↗

bioRxiv2020

SR-B1 uptake of HDL promotes prostate cancer proliferation and tumor progression

High density lipoprotein (HDL) metabolism, in part, is facilitated by scavenger receptor class B, type 1 (SR-B1) that mediates its uptake into cells. SR-B1 is upregulated in prostate cancer tissue. Here, we report that knockout (KO) of SR-B1 via CRISPR/Cas9 editing led to reduced HDL uptake into prostate cancer cells, and reduced their proliferation in response to HDL. In vivo studies using syngeneic SR-B1 wildtype (SR-B1+/+) and SR-B1 KO (SR-B1-/-) prostate cancer cells in WT and apolipoprotein-AI KO (apoA1-KO) C57BL/6J mice showed that WT hosts, containing higher levels of total and HDL-cholesterol, grew larger tumors than apoA1-KO hosts with lower levels of total and HDL-cholesterol. Furthermore, SR-B1-/- prostate cancer cells formed smaller tumors in WT hosts, than SR-B1+/+ cells in same host model. Tumor volume data was overall similar to survival data. We conclude that tumoral SR-B1 KO reduced HDL-mediated increases in prostate cancer cell proliferation and disease progression.

cancer biology↗