ABSTRACT
Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model ( Jmjd3 flox/flox Myh11 CreERT ), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.
ABSTRACT
Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-ß and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.
Subject(s)
Dendritic Cells , Interleukin-6 , Th17 Cells , Wound Healing , Animals , Female , Humans , Male , Mice , Dendritic Cells/immunology , Dendritic Cells/metabolism , Interleukin-17/metabolism , Interleukin-6/metabolism , Jumonji Domain-Containing Histone Demethylases/metabolism , Jumonji Domain-Containing Histone Demethylases/genetics , Mice, Inbred C57BL , Th17 Cells/immunology , Th17 Cells/metabolism , Wound Healing/immunologyABSTRACT
Median arcuate ligament syndrome (MALS) is known to promote arterial collateral circulation development from mesenteric vessel compression and can lead to the development of visceral aneurysms. These aneurysms are often diagnosed at the time of rupture and pose a significant morality risk without appropriate intervention. A celiacomesenteric trunk is a rare anatomic variant in which the celiac artery and superior mesenteric artery share a common origin and has been postulated as a risk factor for developing MALS. In this report, we present a novel case of MALS in a patient with a celiacomesenteric trunk and a superior mesenteric artery aneurysm.
ABSTRACT
Over recent decades, synthetic macrocyclic compounds have attracted interest from the scientific community due to their ability to selectively and reversibly form complexes with a huge variety of guest moieties. These molecules have been studied within a wide range of sensing and other fields. Within this review, we will give an overview of the most common synthetic macrocyclic compounds including cyclodextrins, calixarenes, calixresorcinarenes, pillarenes and cucurbiturils. These species all display the ability to form a wide range of complexes. This makes these compounds suitable in the field of cancer detection since they can bind to either cancer cell surfaces or indeed to marker compounds for a wide variety of cancers. The formation of such complexes allows sensitive and selective detection and quantification of such guests. Many of these compounds also show potential for the detection and encapsulation of environmental carcinogens. Furthermore, many anti-cancer drugs, although effective in in vitro tests, are not suitable for use directly for cancer treatment due to low solubility, inherent instability in in vivo environments or an inability to be adsorbed by or transported to the required sites for treatment. The reversible encapsulation of these species in a macrocyclic compound can greatly improve their solubility, stability and transport to required sites where they can be released for maximum therapeutic effect. Within this review, we intend to present the use of these species both in cancer sensing and treatment. The various macrocyclic compound families will be described, along with brief descriptions of their synthesis and properties, with an outline of their use in cancer detection and usage as therapeutic agents. Their use in the sensing of environmental carcinogens as well as their potential utilisation in the clean-up of some of these species will also be discussed.
Subject(s)
Carcinogens, Environmental , Cyclodextrins , Macrocyclic Compounds , Neoplasms , Receptors, Artificial , Humans , Early Detection of Cancer , Neoplasms/diagnosis , Neoplasms/drug therapySubject(s)
Burnout, Professional , Humans , Burnout, Psychological , Morals , Surveys and Questionnaires , Stress, PsychologicalABSTRACT
OBJECTIVE: To determine macrophage-specific alterations in epigenetic enzyme function contributing to the development of abdominal aortic aneurysms (AAAs). BACKGROUND: AAA is a life-threatening disease, characterized by pathologic vascular remodeling driven by an imbalance of matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Identifying mechanisms regulating macrophage-mediated extracellular matrix degradation is of critical importance to developing novel therapies. METHODS: The role of SET Domain Bifurcated Histone Lysine Methyltransferase 2 (SETDB2) in AAA formation was examined in human aortic tissue samples by single-cell RNA sequencing and in a myeloid-specific SETDB2 deficient murine model induced by challenging mice with a combination of a high-fat diet and angiotensin II. RESULTS: Single-cell RNA sequencing of human AAA tissues identified SETDB2 was upregulated in aortic monocyte/macrophages and murine AAA models compared with controls. Mechanistically, interferon-ß regulates SETDB2 expression through Janus kinase/signal transducer and activator of transcription signaling, which trimethylates histone 3 lysine 9 on the TIMP1-3 gene promoters thereby suppressing TIMP1-3 transcription and leading to unregulated matrix metalloproteinase activity. Macrophage-specific knockout of SETDB2 ( Setdb2f/fLyz2Cre+ ) protected mice from AAA formation with suppression of vascular inflammation, macrophage infiltration, and elastin fragmentation. Genetic depletion of SETDB2 prevented AAA development due to the removal of the repressive histone 3 lysine 9 trimethylation mark on the TIMP1-3 gene promoter resulting in increased TIMP expression, decreased protease activity, and preserved aortic architecture. Lastly, inhibition of the Janus kinase/signal transducer and activator of the transcription pathway with an FDA-approved inhibitor, Tofacitinib, limited SETDB2 expression in aortic macrophages. CONCLUSIONS: These findings identify SETDB2 as a critical regulator of macrophage-mediated protease activity in AAAs and identify SETDB2 as a mechanistic target for the management of AAAs.
Subject(s)
Aortic Aneurysm, Abdominal , Histones , Tissue Inhibitor of Metalloproteinase-3 , Animals , Humans , Mice , Angiotensin II/adverse effects , Angiotensin II/metabolism , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/pathology , Disease Models, Animal , Histone Methyltransferases/metabolism , Histones/adverse effects , Histones/metabolism , Janus Kinases/adverse effects , Janus Kinases/metabolism , Lysine/adverse effects , Lysine/metabolism , Matrix Metalloproteinases/adverse effects , Matrix Metalloproteinases/metabolism , Mice, Inbred C57BL , Mice, Knockout , Tissue Inhibitor of Metalloproteinase-3/geneticsABSTRACT
The role of Reactive Oxygen Species (ROS) on biological media has been shifting over the years, as the knowledge on the complex mechanism that lies in underneath their production and overall results has been growing. It has been known for some time that these species are associated with a number of health conditions. However, they also participate in the immunoactivation cascade process, and can have an active role in theranostics. Macrophages, for example, react to the presence of pathogens through ROS production, potentially allowing the development of new therapeutic strategies. However, their short lifetime and limited spatial distribution of ROS have been limiting factors to the development and understanding of this phenomenon. Even though, ROS have shown successful theranostic applications, e.g., photodynamic therapy, their wide applicability has been hampered by the lack of effective tools for monitoring these processes in real time. Thus the development of innovative sensing strategies for in vivo monitoring of the balance between ROS concentration and the resultant immune response is of the utmost relevance. Such knowledge could lead to major breakthroughs towards the development of more effective treatments for neurodegenerative diseases. Within this review we will present the current understanding on the interaction mechanisms of ROS with biological systems and their overall effect. Additionally, the most promising sensing tools developed so far, for both in vivo and in vitro tracking will be presented along with their main limitations and advantages. This review focuses on the four main ROS that have been studied these are: singlet oxygen species, hydrogen peroxide, hydroxyl radical and superoxide anion.
Subject(s)
Photochemotherapy , Superoxides , Reactive Oxygen Species , Singlet Oxygen , Hydroxyl RadicalABSTRACT
In this article, we summarize key findings from 20 years of research conducted at the intersection of developmental psychology and juvenile justice in the United States. We predominantly examine data from two large-scale, multisite longitudinal studies involving justice-system-involved adolescents-the Pathways to Desistance study and the Crossroads study. Topics of discussion include predictors of offending and desistance from crime; youth outcomes and psychosocial needs; and emerging research, programs, and policy initiatives. First, individual-level (e.g., age, psychosocial maturity) and contextual-level (e.g., antisocial peers, exposure to violence) risk factors associated with offending are explored. Second, we discuss short-term and long-term outcomes of justice-system contact for youths engaging in moderate offenses. We highlight main findings from the Crossroads study indicating that youths who are sanctioned by the justice system at their first arrest have worse outcomes than youths who are diverted from formal processing. Additionally, we discuss the high prevalence of youths' exposure to violence and mental health disorders as well as the differential treatment of youths of color in the justice system. Third, we extend the conversation to justice-system-involved young adults and discuss emerging, innovative legal solutions, including young adult courts. Last, we discuss real-world implications of these findings.
Subject(s)
Law Enforcement , Mental Disorders , Humans , Adolescent , United States/epidemiology , Longitudinal Studies , ViolenceABSTRACT
Little knowledge exists on how evaluators in child custody and child maltreatment cases are informed by guidelines, the kinds of qualifications required and the types of training provided in different countries. The purpose of this paper is to provide an international preliminary comparison on how child custody and child maltreatment risk assessments are conducted in selected Western countries, and how the assessments are informed by best practice guidelines. Another aim is to increase knowledge on how the guidelines and best-practice standards could be developed further to reflect recent research findings. A total number of 18 guidelines were included in the analyses: four from Canada, five from the United States, three from the United Kingdom, three from the Netherlands, two from Finland, and one from Germany. We conducted a content analysis of the included guidelines in the database, focusing on how the guidelines address the best interest of the child criteria, guidelines for conducting the assessments, considerations for evaluative criteria, and specific guidance for conducting specific assessment procedures (e.g., interviews and observations). Findings show that the qualifications of and training provided to evaluators in child custody and child maltreatment risk evaluations are largely heterogeneous across the countries represented. Guidelines differ in whether and how they highlight the importance of evidence-based practices and scientifically validated assessment measures. Implications are drawn from the review and contextualized by international expert authors in the fields of forensic psychology, and family law. After the content analysis, discussion sessions within the expert group were held. The authors provide both commentaries and suggestions to improve the development of standard methods for conducting both child custody and child maltreatment risk evaluations and to consider a more transparent and judicious use of social science research to guide methods and the recommendations offered within these assessments.
ABSTRACT
Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.
Subject(s)
Diabetes Mellitus, Experimental , Mice , Humans , Animals , Mice, Inbred C57BL , Macrophages/metabolism , Wound Healing , Inflammation/metabolism , Cytokines/metabolismABSTRACT
OBJECTIVE: To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs). BACKGROUND: AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development. RESULTS: Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function. CONCLUSIONS: Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs.
Subject(s)
Aortic Aneurysm, Abdominal , Aorta, Abdominal/pathology , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/pathology , Genome-Wide Association Study , Humans , Ligands , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , TranscriptomeABSTRACT
Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial-mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.
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Wound repair following acute injury requires a coordinated inflammatory response. Type I IFN signaling is important for regulating the inflammatory response after skin injury. IFN-κ, a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFN-κ in the context of normal or dysregulated wound healing is unclear. Here, we show that Ifnk expression is upregulated in keratinocytes early after injury and is essential for normal tissue repair. Under diabetic conditions, IFN-κ was decreased in wound keratinocytes, and early inflammation was impaired. Furthermore, we found that the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is upregulated early following injury and regulates Ifnk expression in diabetic wound keratinocytes via an H3K4me3-mediated mechanism. Using a series of in vivo studies with a geneticall y engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Ifnk expression and that Mll1 expression is decreased in T2D keratinocytes. Importantly, we found the administration of IFN-κ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and reepithelialization. These findings have significant implications for understanding the complex role type I IFNs play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest that IFN may be a viable therapeutic target to improve diabetic wound repair.
Subject(s)
Diabetes Mellitus, Type 2 , Interferon Type I , Animals , Humans , Inflammation/metabolism , Mice , Wound Healing/physiologyABSTRACT
Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity and mortality in the setting of acute rupture. Recently, advances in surgical and endovascular repair of AAA have been achieved; however, pharmaceutical therapies to prevent AAA expansion and rupture remain lacking. This highlights an ongoing need to improve the understanding the pathological mechanisms that initiate formation, maintain growth, and promote rupture of AAA. Over the past decade, epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and non-coding RNA, have emerged as important regulators of cellular function. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter cellular phenotypes and have emerged as major intracellular players in a wide range of biological processes. In this review, we discuss the roles and implications of epigenetic modifications in AAA animal models and their relevance to human AAA pathology.
Subject(s)
Aortic Aneurysm, Abdominal , Animals , Aortic Aneurysm, Abdominal/genetics , Aortic Aneurysm, Abdominal/pathology , DNA Methylation , Epigenesis, GeneticABSTRACT
OBJECTIVE: Vascular surgeon-scientists shape the future of our specialty through rigorous scientific investigation and innovation in clinical care and by training the next generation of surgeon-scientists. The Society for Vascular Surgery Foundation (SVSF) supports the development of surgeon-scientists through the Mentored Research Career Development Award (SVSF-CDA) program, providing supplemental funds to recipients of National Institutes of Health (NIH) K08/K23 grants. We evaluated the ongoing success of this mission. METHODS: The curriculum vitae of the 41 recipients of the SVSF supplemental funding from 1999 to 2021 were collected and reviewed to evaluate the academic achievements, define the programmatic accomplishments and return on investment, and identify areas for strategic improvement. RESULTS: For nearly 22 years, the SVSF has awarded supplemental funds for 31 K08 and 10 K23 grants to SVS members from 32 institutions. Of the 41 awardees, 34 have completed their K-funding and 7 are still being supported. Eleven awardees (27%) were women, including six of the current awardees (75%). However, only slight ethnic/racial diversity was found in the program. The awardees had obtained K-funding â¼4 years after becoming faculty. Eleven awardees (27%) were supported by Howard Hughes, NIH F32, or NIH T32 grants during training. To date, the SVSF has committed $12 million to the SVSF-CDA program. Among the 34 who have completed their K-funding, 21 (62%) successfully obtained NIH R01, Veterans Affairs, or Department of Defense funding. The awardees have secured >$114 million in federal funding, representing a 9.5-fold financial return on investment for the SVSF. In addition to research endeavors, 11 awardees (27%) hold endowed professorships and 19 (46%) have secured tenure at their institution. Many of the awardees hold or have held leadership positions, including 18 division chiefs (44%), 11 program directors (27%), 5 chairs of departments of surgery (12%), and 1 dean (2%). Eleven (27%) have served as president of a regional or national society, and 24 (59%) participate in NIH study sections. Of the 34 who have completed their K-funding, 15 (44%) have continued to maintain active independent research funding. CONCLUSIONS: The SVSF-CDA program is highly effective in the development of vascular surgeon-scientists who contribute to the leadership and growth of academic vascular surgery with a 9.5-fold return on investment. The number of female awardees has increased in recent years but ethnic/racial diversity has remained poor. Although 62% successfully transitioned to federal funding, fewer than one half have remained funded over time. Retention in research and increasing diversity for the awardees are major concerns and important areas of strategic focus for the SVSF.
Subject(s)
Awards and Prizes , Biomedical Research/trends , Forecasting , Mentors , Societies, Medical , Surgeons/economics , Vascular Surgical Procedures/trends , Adult , Biomedical Research/economics , Female , Follow-Up Studies , Humans , Leadership , Male , Middle Aged , Research Personnel/economics , Research Personnel/trends , Retrospective Studies , United States , Vascular Surgical Procedures/economicsABSTRACT
COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNß directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic MÏs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNß reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNß/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.
Subject(s)
Coronavirus/metabolism , Diabetes Mellitus, Type 2/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Inflammation Mediators/metabolism , Inflammation/virology , Macrophages/metabolism , Animals , COVID-19/immunology , Coronavirus Infections/genetics , Coronavirus Infections/immunology , Cytokine Release Syndrome , Cytokines/metabolism , Diabetes Mellitus, Type 2/genetics , Female , Histone-Lysine N-Methyltransferase/genetics , Humans , Inflammation/metabolism , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , SARS-CoV-2/metabolism , Signal TransductionABSTRACT
Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-ß regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II-induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.
Subject(s)
Aortic Aneurysm, Abdominal/metabolism , Histone Demethylases/metabolism , Jumonji Domain-Containing Histone Demethylases/metabolism , Macrophages/metabolism , Angiotensin II/pharmacology , Animals , Disease Models, Animal , Inflammation/metabolism , Inflammation Mediators/metabolism , Macrophages/drug effects , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Up-Regulation/drug effects , Up-Regulation/physiologyABSTRACT
BACKGROUND: Complex abdominal aortic aneurysms (AAAs) have traditionally been treated with an open surgical repair (OSR). During the past decade, fenestrated endovascular aneurysm repair (FEVAR) has emerged as a viable option. Hospital procedural volume to outcome relationship for OSR of complex AAAs has been well established, but the impact of procedural volume on FEVAR outcomes remains undefined. This study investigated the outcomes of OSR and FEVAR for the treatment of complex AAAs and examined the hospital volume-outcome relationship for these procedures. METHODS: A retrospective review of a statewide vascular surgery registry was queried for all patients between 2012 and 2018 who underwent elective repair of a juxtarenal/pararenal AAA with FEVAR or OSR. The primary outcomes were 30-day mortality, myocardial infarction, and new dialysis. Secondary end points included postoperative pneumonia, renal dysfunction (creatine concentration increase of >2 mg/dL from preoperative baseline), major bleeding, early procedural complications, length of stay, and need for reintervention. To evaluate procedural volume-outcomes relationship, hospitals were stratified into low- and high-volume aortic centers based on a FEVAR annual procedural volume. To account for baseline differences, we calculated propensity scores and employed inverse probability of treatment weighting in comparing outcomes between treatment groups. RESULTS: A total of 589 patients underwent FEVAR (n = 186) or OSR (n = 403) for a complex AAA. After adjustment, OSR was associated with higher rates of 30-day mortality (10.7% vs 2.9%; P < .001) and need for dialysis (11.3% vs 1.8; P < .001). Postoperative pneumonia (6.8% vs 0.3%; P < .001) and need for transfusion (39.4% vs 10.4%; P < .001) were also significantly higher in the OSR cohort. The median length of stay for OSR and FEVAR was 9 days and 3 days, respectively. For those who underwent FEVAR, endoleaks were present in 12.1% of patients at 30 days and 6.1% of patients at 1 year, with the majority being type II. With a median follow-up period of 331 days (229-378 days), 1% of FEVAR patients required a secondary procedure, and there were no FEVAR conversions to an open aortic repair. Hospitals were divided into low- and high-volume aortic centers based on their annual FEVAR volume of complex AAAs. After adjustment, hospital FEVAR procedural volume was not associated with 30-day mortality or myocardial infarction. CONCLUSIONS: FEVAR was associated with lower perioperative morbidity and mortality compared with OSR for the management of complex AAAs. Procedural FEVAR volume outcome analysis suggests limited differences in 30-day morbidity, although long-term durability warrants further research.
Subject(s)
Aortic Aneurysm, Abdominal/surgery , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Hospitals, High-Volume , Hospitals, Low-Volume , Aged , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/mortality , Blood Vessel Prosthesis , Blood Vessel Prosthesis Implantation/adverse effects , Blood Vessel Prosthesis Implantation/instrumentation , Blood Vessel Prosthesis Implantation/mortality , Endovascular Procedures/adverse effects , Endovascular Procedures/instrumentation , Endovascular Procedures/mortality , Female , Humans , Male , Michigan , Middle Aged , Postoperative Complications/etiology , Prosthesis Design , Registries , Retrospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
Regrowth after fire is critical to the persistence of chaparral shrub communities in southern California, which has been subject to frequent fire events in recent decades. Fires that recur at short intervals of 10 years or less have been considered an inhibitor of recovery and the major cause of 'community type-conversion' in chaparral, primarily based on studies of small extents and limited time periods. However, recent sub-regional investigations based on remote sensing suggest that short-interval fire (SIF) does not have ubiquitous impact on postfire chaparral recovery. A region-wide analysis including a greater spatial extent and time period is needed to better understand SIF impact on chaparral. This study evaluates patterns of postfire recovery across southern California, based on temporal trajectories of Normalized Difference Vegetation Index (NDVI) derived from June-solstice Landsat image series covering the period 1984-2018. High spatial resolution aerial images were used to calibrate Landsat NDVI trajectory-based estimates of change in fractional shrub cover (dFSC) for 294 stands. The objectives of this study were (1) to assess effects of time between fires and number of burns on recovery, using stand-aggregate samples (n = 294) and paired single- and multiple-burn sample plots (n = 528), and (2) to explain recovery variations among predominant single-burn locations based on shrub community type, climate, soils, and terrain. Stand-aggregate samples showed a significant but weak effect of SIF on recovery (p < 0.001; R2 = 0.003). Results from paired sample plots showed no significant effect of SIF on dFSC among twice-burned sites, although recovery was diminished due to SIF at sites that burned three times within 25 years. Multiple linear regression showed that annual precipitation and temperature, chaparral community type, and edaphic variables explain 28% of regional variation in recovery of once-burned sites. Many stands that exhibited poor recovery had burned only once and consist of xeric, desert-fringe chamise in soils of low clay content.