A daily cycle of apocrine secretion by the B cells in the hepatopancreas of terrestrial isopods

1991 ◽  
Vol 69 (7) ◽  
pp. 1931-1937 ◽  
Author(s):  
C. A. C. Hames ◽  
S. P. Hopkin
Keyword(s):  
B Cells ◽  
Cell Types ◽  
Light Cycle ◽  
Daily Cycle ◽  
Porcellio Scaber ◽  
Terrestrial Isopods ◽  
Metal Pollutants ◽  
New Material ◽  
Ultrastructural Appearance ◽  
Two Stages

The ultrastructure of the two cell types of the hepatopancreas of the terrestrial isopods Oniscus asellus and Porcellio scaber was examined at hourly intervals in animals habituated to a 16 h light: 8 h dark cycle. The ultrastructure of the B cells undergoes substantial changes which are repeated every 24 h. This 'B cell cycle' can be divided into two stages. During the first, 'extrusive' stage, which begins about 1 h before the onset of the light period, the contents of the B cells apical to the nuclei are voided into the lumen of the hepatopancreas. The second, 'restitutive,' stage begins about 10 h after the onset of the light cycle. The B cells swell in size by the accumulation of the new material until the next extrusive stage. The ultrastructural appearance of the S cells was similar at all stages of the daily and moult cycles; they were never observed to void any material into the lumen of the hepatopancreas. The differences between the rates of turnover of the contents of the S and B cells have important implications for understanding the dynamics of accumulation and loss of metal pollutants in terrestrial isopods.

Ca++-ATPase activity in the hepatopancreas cells of Oniscus asellus

1992 ◽  
Vol 50 (1) ◽  
pp. 820-821
Author(s):  
G.M. Vernon ◽  
A. Surace ◽  
R. Witkus
Keyword(s):  
B Cells ◽  
Epithelial Cell ◽  
Atpase Activity ◽  
Calcium Transport ◽  
Carcinus Maenas ◽  
Cell Types ◽  
Molt Cycle ◽  
Copper And Zinc

The hepatopancreas consists of a pair of bilobed tubules comprised of two epithelial cell types. S cells are absorptive and accumulate metals such as copper and zinc. Ca++ concentrations vary between the S and B cells and during the molt cycle. Roer and Dillaman implicated Ca++-ATPase in calcium transport during molting in Carcinus maenas. This study was undertaken to compare the localization of Ca++-ATPase activity in the S and B cells during intermolt.

scholarly journals 521. Similarities and Differences in Transcriptomic Host Response between SARS-CoV-2 and Other Viral Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S326-S327
Author(s):  
Simone A Thair ◽  
Yudong He ◽  
Yehudit Hasin-Brumshtein ◽  
Suraj Sakaram ◽  
Rushika R Pandya ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Nk Cells ◽  
Pathway Analysis ◽  
Host Response ◽  
Viral Infections ◽  
Cell Types ◽  
Gene Signature ◽  
Gene Signatures ◽  
Similarities And Differences

Abstract Background COVID-19 is a pandemic caused by the SARS-CoV-2 virus that shares and differs in clinical characteristics of known viral infections. Methods We obtained RNAseq profiles of 62 prospectively enrolled COVID-19 patients and 24 healthy controls (HC). We collected 23 independent studies profiling 1,855 blood samples from patients covering six viruses (influenza, RSV, HRV, Ebola, Dengue and SARS-CoV-1). We studied host whole-blood transcriptomic responses in COVID-19 compared to non-COVID-19 viral infections to understand similarities and differences in host response. Gene signature threshold was absolute effect size ≥1, FDR ≤ 0.05%. Results Differential gene expression of COVID-19 vs HC are highly correlated with non-COVID-19 vs HC (r=0.74, p< 0.001). We discovered two gene signatures: COVID-19 vs HC (2002 genes) (COVIDsig) and non-COVID-19 vs HC (635 genes) (nonCOVIDsig). Pathway analysis of over-expressed signature genes in COVIDsig or nonCOVIDsig identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection and cytokine production. Conversely, for under-expressed genes, pathways indicated repression of lymphocyte differentiation and activation (Fig1). Intersecting the two gene signatures found two genes significantly oppositely regulated (ACO1, ATL3). We derived a third gene signature using COCONUT to compare COVID-19 to non-COVID-19 viral infections (416 genes) (Fig2). Pathway analysis did not result in significant enrichment, suggesting identification of novel biology (Fig1). Statistical deconvolution of bulk transcriptomic data found M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells and total B cells changed in the same direction across COVID-19 and non-COVID-19 infections. Cell types that increased in COVID-19 relative to non-COVID-19 were CD56bright NK cells, M2 macrophages and total NK cells. Those that decreased in non-COVID-19 relative to COVID-19 were CD56dim NK cells & memory B cells and eosinophils (Fig3). Figure 1 Figure 2 Figure 3 Conclusion The concordant and discordant responses mapped here provide a window to explore the pathophysiology of COVID-19 vs other viral infections and show clear differences in signaling pathways and cellularity as part of the host response to SARS-CoV-2. Disclosures Simone A. Thair, PhD, Inflammatix, Inc. (Employee, Shareholder) Yudong He, PhD, Inflammatix Inc. (Employee) Yehudit Hasin-Brumshtein, PhD, Inflammatix (Employee, Shareholder) Suraj Sakaram, MS in Biochemistry and Molecular Biology, Inflammatix (Employee, Other Financial or Material Support, stock options) Rushika R. Pandya, MS, Inflammatix Inc. (Employee, Shareholder) David C. Rawling, PhD, Inflammatix Inc. (Employee, Shareholder) Purvesh Khatri, PhD, Inflammatix Inc. (Shareholder) Timothy Sweeney, MD, PHD, Inflammatix, Inc. (Employee, Shareholder)

scholarly journals Occurrence of the Isopod Iridovirus in European Armadillidium and Porcellio (Crustacea, Isopoda)

1985 ◽  
Vol 55 (2) ◽  
pp. 280-282 ◽  
Author(s):  
George O. Poinar ◽  
Roberta T. Hess ◽  
Jan H. Stock
Keyword(s):  
The Netherlands ◽  
First Record ◽  
Blue Color ◽  
Porcellio Scaber ◽  
Terrestrial Isopods ◽  
Armadillidium Vulgare ◽  
Bright Blue

First record of iridovirus infections of terrestrial isopods (Armadillidium vulgare and Porcellio scaber) in Europe (The Netherlands). Infested specimens can be detected by their bright blue color.

scholarly journals Phenotype of recovering lymphoid cell populations after marrow transplantation.

1985 ◽  
Vol 161 (6) ◽  
pp. 1483-1502 ◽  
Author(s):  
K A Ault ◽  
J H Antin ◽  
D Ginsburg ◽  
S H Orkin ◽  
J M Rappeport ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Nk Cells ◽  
Cell Types ◽  
Lymphoid Cells ◽  
The Other ◽  
Hla Dr ◽  
T Cell Antigens ◽  
Leu 7

Four patients who received bone marrow transplants were studied sequentially during the posttransplant period to define the pattern of recovering lymphoid cell types. Three patients received T cell-depleted, HLA-matched marrow, and one received untreated marrow from an identical twin. Blood lymphoid cells were labeled with 25 different pairs of monoclonal antibodies. In each sample, one antibody was conjugated to fluorescein and one to phycoerythrin, thus allowing simultaneous assessment of the expression of the two markers using the fluorescence activated cell sorter. A total of 14 antibodies were used, routinely including HLE, Leu-M3, Leu-4, Leu-1, Leu-5, Leu-9, Leu-6, Leu-2, Leu-3, HLA-DR, Leu-7, Leu-11, Leu-15, and Leu-12. Other antibodies were used to further define some populations. This study has allowed us to define six distinct cell types that have appeared in all four patients by day 90 posttransplantation, and which account for 90-100% of all circulating lymphoid cells. These cell types are (a) T helper cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-3, and variable amounts of HLA-DR; (b) T suppressor cells expressing Leu-1, Leu-4, Leu-9, Leu-5, Leu-2, and variable amounts of HLA-DR; (c) B cells expressing Leu-12, B1, HLA-DR, IgD, and IgM, but none of the T cell antigens; (d) an unusual B cell phenotype (Leu-1 B) expressing all of the B cell markers, and also having low amounts of Leu-1, but none of the other T cell antigens; (e) natural killer (NK) cells expressing Leu-11, Leu-15, Leu-5 but none of the other T cell or B cell markers; (f) NK cells expressing Leu-11, Leu-15, Leu-5, and low levels of Leu-2. Both NK types also express Leu-7 on some, but not all cells. The relative frequencies of these cell types varied among the patients and with time, but the striking findings were the presence of relatively few mature T cells, large numbers of NK cells, and the preponderance of the unusual Leu-1 B cell over conventional B cells in all three patients who developed B cells. Sorting experiments confirmed the NK activity of the major NK cell phenotypes, and DNA analysis confirmed that all of the cells studied were of donor origin. In addition, analysis of Ig genes in one patient showed that the Leu-1 B cells were not clonally rearranged.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Th2 Cytokine Modulates Herpesvirus Reactivation in a Cell Type Specific Manner

2021 ◽  
Author(s):  
Guoxun Wang ◽  
Christina Zarek ◽  
Tyron Chang ◽  
Lili Tao ◽  
Alexandria Lowe ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Types ◽  
The Body ◽  
Receptor Expression ◽  
Conditional Knockout ◽  
Interleukin 4 ◽  
Virus Reactivation ◽  
Cell Type ◽  
Murine Gammaherpesvirus ◽  
Cell Type Specific

Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposi’s sarcoma associated virus (KSHV), and murine γ-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an in vivo approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds virus gene 50 N4/N5 promoter in macrophages, did not bind to the virus gene 50 N4/N5 promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others. Importance Herpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.

scholarly journals High Dimensional Tissue-Based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Jose C Villasboas ◽  
Patrizia Mondello ◽  
Angelo Fama ◽  
Melissa C. Larson ◽  
Andrew L. Feldman ◽  
...  
Keyword(s):  
T Cells ◽  
Spatial Distribution ◽  
T Cell ◽  
B Cells ◽  
Research Funding ◽  
Memory T Cells ◽  
Cell Types ◽  
T Cell Subsets ◽  
Cell Contact ◽  
Private Company

Background The importance of the immune system in modulating the trajectory of lymphoma outcomes has been increasingly recognized. We recently showed that CD4+ cells are associated with clinical outcomes in a prospective cohort of almost 500 patients with follicular lymphoma (FL). Specifically, we showed that the absence of CD4+ cells inside follicles was independently associated with increased risk of early clinical failure. These data suggest that the composition, as well as the spatial distribution of immune cells within the tumor microenvironment (TME), play an important role in FL. To further define the architecture of the TME in FL we analyzed a FL tumor section using the Co-Detection by Indexing (CODEX) multiplex immunofluorescence system. Methods An 8-micron section from a formalin-fixed paraffin-embedded block containing a lymph node specimen from a patient with FL was stained with a cocktail of 15 CODEX antibodies. Five regions of interest (ROIs) were imaged using a 20X air objective. Images underwent single-cell segmentation using a Unet neural network, trained on manually segmented cells (Fig 1A). Cell type assignment was done after scaling marker expression and clustering using Phenograph. Each ROI was manually masked to indicate areas inside follicles (IF) and outside follicles (OF). Relative and absolute frequencies of cell types were calculated for each region. Cellular contacts were measured as number and types of cell-cell contacts within two cellular diameters. To identify proximity communities, we clustered cells based on number and type of neighboring masks using Phenograph. The number of cell types and cellular communities were calculated inside and outside follicles after adjustment for total IF and OF areas. The significance of cell contact was measured using a random permutation test. Results We identified 13 unique cell subsets (11 immune, 1 endothelial, 1 unclassified) in the TME of our FL section (Fig. 1A). The unique phenotype of each subset was confirmed using a dimensionality reduction tool (t-SNE). The global composition of the TME varied minimally across ROIs and consisted primarily of B cells, T cells, and macrophages subsets - in decreasing order of frequency. Higher spatial heterogeneity across ROIs was observed in the frequency of T cell subsets in comparison to B cells subsets. Inspecting the spatial distribution of T cell subsets (Fig. 1B), we observed that cytotoxic T cells were primarily located in OF areas, whereas CD4+ T cells were found in both IF and OF areas. Notably, the majority of CD4+ T cells inside the follicles expressed CD45RO (memory phenotype), while most of the CD4+ T cells outside the follicles did not. Statistical analysis of the spatial distribution of CD4+ memory T cell subsets confirmed a significant increase in their frequency inside follicles compared to outside (20.4% vs 11.2%, p < 0.001; Fig. 1D). Cell-cell contact analysis (Fig 1C) showed increased homotypic contact for all cell types. We also found a higher frequency of heterotypic contact between Ki-67+CD4+ memory T cells and Ki-67+ B cells. Pairwise analysis showed these findings were statistically significant, indicating these cells are organized in niches rather than randomly distributed across image. Analysis of cellular communities (Fig. 1C) identified 13 niches, named according to the most frequent type of cell-cell contact. All CD4+ memory T cell subsets were found to belong to the same neighborhood (CD4 Memory community). Analysis of the spatial distribution of this community confirmed that these niches were more frequently located inside follicles rather than outside (26.3±4% vs 0.004%, p < 0.001, Fig. 1D). Conclusions Analysis of the TME using CODEX provides insights on the complex composition and unique architecture of this FL case. Cells were organized in a pattern characterized by (1) high degree of homotypic contact and (2) increased heterotypic interaction between activated B cells and activated CD4+ memory T cells. Spatial analysis of both individual cell subsets and cellular neighborhoods demonstrate a statistically significant increase in CD4+ memory T cells inside malignant follicles. This emerging knowledge about the specific immune-architecture of FL adds mechanistic details to our initial observation around the prognostic value of the TME in this disease. These data support future studies using modulation of the TME as a therapeutic target in FL. Figure 1 Disclosures Galkin: BostonGene: Current Employment, Patents & Royalties. Svekolkin:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Postovalova:BostonGene: Current Employment, Current equity holder in private company. Bagaev:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Ovcharov:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Varlamova:BostonGene: Current Employment, Current equity holder in private company, Patents & Royalties. Novak:Celgene/BMS: Research Funding. Witzig:AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Nanostrings: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Kymera: Consultancy; Denovo: Consultancy; Kite: Consultancy; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Ansell:Trillium: Research Funding; Takeda: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4703-4712 ◽  
Author(s):  
Jennifer L. Costantini ◽  
Samuel M. S. Cheung ◽  
Sen Hou ◽  
Hongzhao Li ◽  
Sam K. Kung ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Cell Types ◽  
Potential Interaction ◽  
Cytoskeletal Proteins ◽  
Lymphocytic Leukemia ◽  
Pleckstrin Homology Domain ◽  
Ph Domain

Abstract Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking. The association of TAPP2 with the cytoskeletal proteins utrophin and syntrophin was confirmed by Western blotting. We found that TAPP2, syntrophin, and utrophin are coexpressed in normal human B cells and B-chronic lymphocytic leukemia (B-CLL) cells. TAPP2 and syntrophin expression in B-CLL was variable from patient to patient, with significantly higher expression in the more aggressive disease subset identified by zeta-chain–associated protein kinase of 70 kDa (ZAP70) expression and unmutated immunoglobulin heavy chain (IgH) genes. We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain–mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression.

The function of the neurogenic genes during epithelial development in the Drosophila embryo

Development ◽  
1992 ◽  
Vol 116 (4) ◽  
pp. 1203-1220 ◽  
Author(s):  
A.Y. Hartenstein ◽  
A. Rugendorff ◽  
U. Tepass ◽  
V. Hartenstein
Keyword(s):  
Fat Body ◽  
Cell Types ◽  
Malpighian Tubules ◽  
Drosophila Embryo ◽  
Stomatogastric Nervous System ◽  
Mesodermal Cell ◽  
Epithelial Phenotype ◽  
In The Wild ◽  
Two Stages ◽  
Enhancer Of Split

The complex embryonic phenotype of the six neurogenic mutations Notch, mastermind, big brain, Delta, Enhancer of split and neuralized was analyzed by using different antibodies and PlacZ markers, which allowed us to label most of the known embryonic tissues. Our results demonstrate that all of the neurogenic mutants show abnormalities in many different organs derived from all three germ layers. Defects caused by the neurogenic mutations in ectodermally derived tissues fell into two categories. First, all cell types that delaminate from the ectoderm (neuroblasts, sensory neurons, peripheral glia cells and oenocytes) are increased in number. Secondly, ectodermal tissues that in the wild type form epithelial structures lose their epithelial phenotype and dissociate (optic lobe, stomatogastric nervous system) or show significant differentiative abnormalities (trachea, Malpighian tubules and salivary gland). Abnormalities in tissues derived from the mesoderm were observed in all six neurogenic mutations. Most importantly, somatic myoblasts do not fuse and/or form an aberrant muscle pattern. Cardioblasts (which form the embryonic heart) are increased in number and show differentiative abnormalities; other mesodermal cell types (fat body, pericardial cells) are significantly decreased. The development of the endoderm (midgut rudiments) is disrupted in most of the neurogenic mutations (Notch, Delta, Enhancer of split and neuralized) during at least two stages. Defects occur as early as during gastrulation when the invaginating midgut rudiments prematurely lose their epithelial characteristics. Later, the transition of the midgut rudiments to form the midgut epithelium does not occur. In addition, the number of adult midgut precursor cells that segregate from the midgut rudiments is strongly increased. We propose that, at least in the ectodermally and endodermally derived tissues, neurogenic gene function is primarily involved in interactions among cells that need to acquire or to maintain an epithelial phenotype.

Localization of Enzymes in Certain Secretory Cells of Helix Tentacles

1964 ◽  
Vol s3-105 (69) ◽  
pp. 49-60
Author(s):  
NANCY J. LANE
Keyword(s):  
Alkaline Phosphatase ◽  
Acid Phosphatase ◽  
Cell Types ◽  
Secretory Cells ◽  
Oval Cells ◽  
Cytoplasmic Localization ◽  
Cell Organelles ◽  
Distinct Cell ◽  
Thiamine Pyrophosphatase ◽  
Ultrastructural Appearance

Secretory cells in the optic tentacles of the snails, Helix aspersa and H. pomatia, have been investigated for the cytoplasmic localization of certain enzymes. The collar cells, considered to be neurosecretory, and the lateral oval cells, were those examined. Acid phosphatase activity is found in the cytoplasm of both cells, in scattered spheroids called the β-bodies. This enzymatic activity indicates that the β-bodies may be lysosomes, as does their ultrastructural appearance. In the 2 cell types, the activity of both alkaline phosphatase and thiamine pyrophosphatase is localized in crescentic bodies considered to correspond to the Golgi lamellae, and in some of the β-bodies. The latter enzyme also exists in the cortices of the α-bodies which, like the β-bodies, are lipid-containing globules. The activity of both cytochrome oxidase and succinate dehydrogenase is found, not only in granules, rods, and filaments interpreted as the mitochondria, but also on the cortices of some or all of the β-bodies. It is concluded that in invertebrates, the lipochondria may be the sites of activity of many different enzymes which in vertebrates are restricted to distinct cell organelles.

Abstract 3: Cellular Contributions of the Circadian Clock in Atherogenesis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xueling Li ◽  
Ling Ruan ◽  
Austin Bentley ◽  
Stephen Haigh ◽  
Yuqing Huo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
Circadian Rhythm ◽  
Circadian Clock ◽  
Cell Types ◽  
No Production ◽  
Light Cycle ◽  
Lipid Uptake ◽  
Enhanced Production ◽  
The Impact

Atherosclerosis is a leading cause of death despite the improvements in lipid and blood pressure control. The circadian clock, a molecular network of genes and proteins that controls 24-hour timing, has emerged to have a surprising role in the control of metabolic and vascular function. Herein we examined the impact of circadian rhythm dysfunction in atherogenesis by implementation of vascular transplant and PCSK9 based approaches to induce accelerated lesion development in mice. We find that atherogenesis is exacerbated in Bmal1-KO aortic grafts immersed in the hypercholesterolemic milieu of ApoE -/- mice. To assess if atherosclerosis was ‘circadian rhythm dependent’ we subjected wild-type mice to a shortened light cycle (4L/4D) and induced atherosclerosis by intravenous injection of a human PCSK-9 adeno associated virus. Atherosclerosis in the jet-lagged PCSK-9 mice was robustly increased relative to the atherosclerosis observed in WT mice on a normal light cycle (12L/12D), providing further evidence that circadian rhythm and the circadian clock contribute to atherosclerosis. However, atherosclerosis is a complex disease that is the net result of interplay between intrinsic (vascular cells) and extrinsic mechanisms (metabolism, blood pressure, and hormones) and the importance of clock function in individual cell types is poorly understood. We found that deletion or silencing of key circadian transcription factors resulted in an enhanced inflammatory and pro-oxidant phenotype with diminished NO production and greater lipid uptake in both macrophages and endothelial cells. Loss of circadian function in smooth muscle cells similarly resulted in enhanced production of reactive oxygen species and greater cell proliferation. Surprising, the silencing of Bmal2 in endothelial cells resulted in greater lipid uptake in oxLDL treated HAEC as well as increased expression of markers of autophagy, suggesting that Bmal2 may orchestrate numerous output functions in different cell types. In conclusion, we find that the circadian clock and circadian rhythm have a profound impact on atherosclerosis, to influence vascular cell inflammatory and lipid uptake responses, and identify an unexpectedly prominent role for the side-partner of Bmal1, Bmal2.

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