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Forty-Year Anniversary of Arteriosclerosis, Thrombosis, and Vascular Biology

Daugherty, Alan; Fisher, Edward A; Taubman, Mark B; Heistad, Donald D; Fogelman, Alan M
PMID: 34432483
ISSN: 1524-4636
CID: 4989112

Silencing Myeloid Netrin-1 Induces Inflammation Resolution and Plaque Regression

Schlegel, Martin Paul; Sharma, Monika; Brown, Emily J; Newman, Alexandra Ac; Cyr, Yannick; Afonso, Milessa Silva; Corr, Emma M; Koelwyn, Graeme J; van Solingen, Coen; Guzman, Jonathan; Farhat, Rubab; Nikain, Cyrus A; Shanley, Lianne C; Peled, Daniel; Schmidt, Ann Marie; Fisher, Edward A; Moore, Kathryn J
PMID: 34289717
ISSN: 1524-4571
CID: 4948372

Two-Photon, Ratiometric, Quantitative Fluorescent Probe Reveals Fluctuation of Peroxynitrite Regulated by Arginase 1

Chen, Shiyu; Vurusaner, Beyza; Pena, Stephanie; Thu, Chu T; Mahal, Lara K; Fisher, Edward A; Canary, James W
Peroxynitrite, a transient reactive oxygen species (ROS), is believed to play a deleterious role in physiological processes. Herein, we report a two-photon ratiometric fluorescent probe that selectively reacts with peroxynitrite yielding a >200-fold change upon reaction. The probe effectively visualized fluctuations in peroxynitrite generation by arginase 1 in vivo and in vitro. This provides evidence that arginase 1 is a critical regulator of peroxynitrite.
PMID: 34269045
ISSN: 1520-6882
CID: 4937572

Fate and State of Vascular Smooth Muscle Cells in Atherosclerosis

Miano, Joseph M; Fisher, Edward A; Majesky, Mark W
Vascular smooth muscle cells (VSMCs) have long been associated with phenotypic modulation/plasticity or dedifferentiation. Innovative technologies in cell lineage tracing, single-cell RNA sequencing, and human genomics have been integrated to gain unprecedented insights into the molecular reprogramming of VSMCs to other cell phenotypes in experimental and clinical atherosclerosis. The current thinking is that an apparently small subset of contractile VSMCs undergoes a fate switch to transitional, multipotential cells that can adopt plaque-destabilizing (inflammation, ossification) or plaque-stabilizing (collagen matrix deposition) cell states. Several candidate mediators of such VSMC fate and state changes are coming to light with intriguing implications for understanding coronary artery disease risk and the development of new treatment modalities. Here, we briefly summarize some technical and conceptual advancements derived from 2 publications in Circulation and another in Nature Medicine that, collectively, illuminate new research directions to further explore the role of VSMCs in atherosclerotic disease.
PMID: 34029141
ISSN: 1524-4539
CID: 4902982

Reshaping of the gastrointestinal microbiome alters atherosclerotic plaque inflammation resolution in mice

Garshick, Michael S; Nikain, Cyrus; Tawil, Michael; Pena, Stephanie; Barrett, Tessa J; Wu, Benjamin G; Gao, Zhan; Blaser, Martin J; Fisher, Edward A
Since alterations in the intestinal microbiota may induce systemic inflammation and polarization of macrophages to the M1 state, the microbiome role in atherosclerosis, an M1-driven disease, requires evaluation. We aimed to determine if antibiotic (Abx) induced alterations to the intestinal microbiota interferes with atherosclerotic plaque inflammation resolution after lipid-lowering in mice. Hyperlipidemic Apoe-/- mice were fed a western diet to develop aortic atherosclerosis with aortas then transplanted into normolipidemic wild-type (WT) mice to model clinically aggressive lipid management and promote atherosclerosis inflammation resolution. Gut microbial composition pre and post-transplant was altered via an enteral antibiotic or not. Post aortic transplant, after Abx treatment, while plaque size did not differ, compared to Apoe-/- mice, Abx- WT recipient mice had a 32% reduction in CD68-expressing cells (p = 0.02) vs. a non-significant 12% reduction in Abx+ WT mice. A trend toward an M1 plaque CD68-expresing cell phenotype was noted in Abx+ mice. By 16S rRNA sequence analysis, the Abx+ mice had reduced alpha diversity and increased Firmicutes/Bacteroidetes relative abundance ratio with a correlation between gut Firmicutes abundance and plaque CD68-expressing cell content (p < 0.05). These results indicate that in a murine atherosclerotic plaque inflammation resolution model, antibiotic-induced microbiome perturbation may blunt the effectiveness of lipid-lowering to reduce the content of plaque inflammatory CD68-expressing cells.
PMID: 33903700
ISSN: 2045-2322
CID: 4889262

miR-33 Silencing Reprograms the Immune Cell Landscape in Atherosclerotic Plaques

Afonso, Milessa Silva; Sharma, Monika; Schlegel, Martin Paul; van Solingen, Coen; Koelwyn, Graeme J; Shanley, Lianne C; Beckett, Lauren; Peled, Daniel; Rahman, Karishma; Giannarelli, Chiara; Li, Huilin; Brown, Emily J; Khodadadi-Jamayran, Alireza; Fisher, Edward A; Moore, Kathryn J
Rationale: MicroRNA-33 post-transcriptionally represses genes involved in lipid metabolism and energy homeostasis. Targeted inhibition of miR-33 increases plasma HDL cholesterol and promotes atherosclerosis regression, in part, by enhancing reverse cholesterol transport and dampening plaque inflammation. However, how miR-33 reshapes the immune microenvironment of plaques remains poorly understood. Objective: To define how miR-33 inhibition alters the dynamic balance and transcriptional landscape of immune cells in atherosclerotic plaques. Methods and Results: We used single cell RNA-sequencing of aortic CD45+ cells, combined with immunohistologic, morphometric and flow cytometric analyses to define the changes in plaque immune cell composition, gene expression and function following miR-33 inhibition. We report that anti-miR-33 treatment of Ldlr-/- mice with advanced atherosclerosis reduced plaque burden and altered the plaque immune cell landscape by shifting the balance of pro- and anti-atherosclerotic macrophage and T cell subsets. By quantifying the kinetic processes that determine plaque macrophage burden, we found that anti-miR-33 reduced levels of circulating monocytes and splenic myeloid progenitors, decreased macrophage proliferation and retention, and promoted macrophage attrition by apoptosis and efferocytotic clearance. scRNA-sequencing of aortic arch plaques showed that anti-miR-33 reduced the frequency of MHCIIhi "inflammatory" and Trem2hi "metabolic" macrophages, but not tissue resident macrophages. Furthermore, anti-miR-33 led to derepression of distinct miR-33 target genes in the different macrophage subsets: in resident and Trem2hi macrophages, anti-miR-33 relieved repression of miR-33 target genes involved in lipid metabolism (e.g., Abca1, Ncoa1, Ncoa2, Crot), whereas in MHCIIhi macrophages, anti-miR-33 upregulated target genes involved in chromatin remodeling and transcriptional regulation. Anti-miR-33 also reduced the accumulation of aortic CD8+ T cells and CD4+ Th1 cells, and increased levels of FoxP3+ regulatory T cells in plaques, consistent with an immune-dampening effect on plaque inflammation. Conclusions: Our results provide insight into the immune mechanisms and cellular players that execute anti-miR-33's atheroprotective actions in the plaque.
PMID: 33593073
ISSN: 1524-4571
CID: 4786732

Diabetes and Metabolic Drivers of Trained Immunity: New Therapeutic Targets Beyond Glucose

Choudhury, Robin P; Edgar, Laurienne; Rydén, Mikael; Fisher, Edward A
[Figure: see text].
PMID: 33657881
ISSN: 1524-4636
CID: 4862012

CCL20 in Psoriasis: A Potential Biomarker of Disease Severity, Inflammation, and Impaired Vascular Health

Elnabawi, Youssef A; Garshick, Michael S; Tawil, Michael; Barrett, Tessa J; Fisher, Edward A; Lo Sicco, Kristen; Neimann, Andrea L; Scher, Jose U; Krueger, James; Berger, Jeffrey S
BACKGROUND:Psoriasis is associated with increased cardiovascular risk that is not captured by traditional pro-inflammatory biomarkers. OBJECTIVE:To investigate the relationship between psoriasis area and severity index (PASI), circulating pro-inflammatory biomarkers, and vascular health in psoriasis. METHODS:In psoriasis and age, sex-matched controls, 273 proteins were analyzed utilizing the OLINK platform, while vascular endothelial inflammation and health was measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS:= 48.18, p<0.001) in predicting vascular endothelial inflammation. LIMITATIONS/CONCLUSIONS:Our study was observational and does not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION/CONCLUSIONS:We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.
PMID: 33259876
ISSN: 1097-6787
CID: 4694102

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice

Voisin, Maud; Shrestha, Elina; Rollet, Claire; Nikain, Cyrus A; Josefs, Tatjana; Mahé, Mélanie; Barrett, Tessa J; Chang, Hye Rim; Ruoff, Rachel; Schneider, Jeffrey A; Garabedian, Michela L; Zoumadakis, Chris; Yun, Chi; Badwan, Bara; Brown, Emily J; Mar, Adam C; Schneider, Robert J; Goldberg, Ira J; Pineda-Torra, Inés; Fisher, Edward A; Garabedian, Michael J
Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
PMID: 33772096
ISSN: 2399-3642
CID: 4823692

Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice

Josefs, Tatjana; Basu, Debapriya; Vaisar, Tomas; Arets, Britt; Kanter, Jenny E; Huggins, Lesley-Ann; Hu, Yunying; Liu, Jianhua; Clouet-Foraison, Noemie; Heinecke, Jay W; Bornfeldt, Karin E; Goldberg, Ira J; Fisher, Edward A
[Figure: see text].
PMID: 33530703
ISSN: 1524-4571
CID: 4850882