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A Randomized Open Label Clinical Trial of Lipid-Lowering Therapy in Psoriasis to Reduce Vascular Endothelial Inflammation

Garshick, Michael S; Drenkova, Kamelia; Barrett, Tessa J; Schlamp, Florencia; Fisher, Edward A; Katz, Stuart; Jelic, Sanja; Neimann, Andrea L; Scher, Jose U; Krueger, James; Berger, Jeffrey S
PMID: 34808233
ISSN: 1523-1747
CID: 5063372

Emerging Concepts of Vascular Cell Clonal Expansion in Atherosclerosis

Misra, Ashish; Rehan, Rajan; Lin, Alexander; Patel, Sanjay; Fisher, Edward A
Clonal expansion is a process that can drive pathogenesis in human diseases, with atherosclerosis being a prominent example. Despite advances in understanding the etiology of atherosclerosis, clonality studies of vascular cells remain in an early stage. Recently, several paradigm-shifting preclinical studies have identified clonal expansion of progenitor cells in the vasculature in response to atherosclerosis. This review provides an overview of cell clonality in atherosclerotic progression, focusing particularly on smooth muscle cells and macrophages. We discuss key findings from the latest research that give insight into the mechanisms by which clonal expansion of vascular cells contributes to disease pathology. The further probing of these mechanisms will provide innovative directions for future progress in the understanding and therapy of atherosclerosis and its associated cardiovascular diseases.
PMID: 35109671
ISSN: 1524-4636
CID: 5153622

Deficiency of inactive rhomboid protein 2 (iRhom2) attenuates diet-induced hyperlipidemia and early atherogenesis

Hannemann, Carmen; Schecker, Johannes H; Brettschneider, Alica; Grune, Jana; Rösener, Nicole; Weller, Andrea; Stangl, Verena; Fisher, Edward A; Stangl, Karl; Ludwig, Antje; Hewing, Bernd
AIMS/OBJECTIVE:Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumor necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis. METHODS AND RESULTS/RESULTS:Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks of WD. Analyses of hepatic bile acid concentration and gene expression at 8 weeks of WD revealed that iRhom2 deficiency prevented WD-induced repression of hepatic bile acid synthesis in LDLR-/- mice. In contrast, at 20 weeks of WD plaque size, plaque composition, and serum levels of TNF-α or cholesterol were not different between genotypes. CONCLUSIONS:Modulation of inflammation by iRhom2 deficiency attenuated diet induced hyperlipidemia and early atherogenesis in LDLR-/- mice. iRhom2 deficiency did not affect diet- induced plaque burden and composition in advanced atherosclerosis in LDLR-/- mice. TRANSLATIONAL PERSPECTIVE/UNASSIGNED:iRhom2 attenuates shedding of TNF-α selectively from immune cells and therefore has emerged as a potential new target for the treatment of inflammatory diseases. In the present study, we identified iRhom2 as a critical link between inflammation, lipid metabolism, and atherogenesis. Selective iRhom2 inhibition represents a potential treatment strategy to modify atherosclerosis, particularly in the presence of enhanced inflammation as observed with diabetes mellitus or rheumatoid arthritis.
PMID: 33576385
ISSN: 1755-3245
CID: 4806462

Hsp40s play distinct roles during the initial stages of apolipoprotein B biogenesis

Kumari, Deepa; Fisher, Edward A; Brodsky, Jeffrey L
Apolipoprotein B (ApoB) is the primary component of atherogenic lipoproteins, which transport serum fats and cholesterol. Therefore, elevated levels of circulating ApoB are a primary risk factor for cardiovascular disease. During ApoB biosynthesis in the liver and small intestine under nutrient-rich conditions, ApoB cotranslationally translocates into the endoplasmic reticulum (ER) and is lipidated and ultimately secreted. Under lipid-poor conditions, ApoB is targeted for ER Associated Degradation (ERAD). Although prior work identified select chaperones that regulate ApoB biogenesis, the contributions of cytoplasmic Hsp40s are undefined. To this end, we screened ApoB-expressing yeast and determined that a class A ER-associated Hsp40, Ydj1, associates with and facilitates the ERAD of ApoB. Consistent with these results, a homologous Hsp40, DNAJA1, functioned similarly in rat hepatoma cells. DNAJA1 deficient cells also secreted hyperlipidated lipoproteins, in accordance with attenuated ERAD. In contrast to the role of DNAJA1 during ERAD, DNAJB1-a class B Hsp40-helped stabilize ApoB. Depletion of DNAJA1 and DNAJB1 also led to opposing effects on ApoB ubiquitination. These data represent the first example in which different Hsp40s exhibit disparate effects during regulated protein biogenesis in the ER, and highlight distinct roles that chaperones can play on a single ERAD substrate.
PMID: 34910568
ISSN: 1939-4586
CID: 5109762

Chronic stress primes innate immune responses in mice and humans

Barrett, Tessa J; Corr, Emma M; van Solingen, Coen; Schlamp, Florencia; Brown, Emily J; Koelwyn, Graeme J; Lee, Angela H; Shanley, Lianne C; Spruill, Tanya M; Bozal, Fazli; de Jong, Annika; Newman, Alexandra A C; Drenkova, Kamelia; Silvestro, Michele; Ramkhelawon, Bhama; Reynolds, Harmony R; Hochman, Judith S; Nahrendorf, Matthias; Swirski, Filip K; Fisher, Edward A; Berger, Jeffrey S; Moore, Kathryn J
Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.
PMID: 34496250
ISSN: 2211-1247
CID: 5012012

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