Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling.

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.

Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells.

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.

Superior mesenteric aneurysm associated with median arcuate ligament syndrome and a single celiacomesenteric trunk.

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.

The Histone Methyltransferase SETDB2 Modulates Tissue Inhibitors of Metalloproteinase-Matrix Metalloproteinase Activity During Abdominal Aortic Aneurysm Development.

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.

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair.

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.

Single-cell Transcriptomics Reveals Dynamic Role of Smooth Muscle Cells and Enrichment of Immune Cell Subsets in Human Abdominal Aortic Aneurysms.

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.

IFN-κ is critical for normal wound repair and is decreased in diabetic wounds.

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.

The Role of Epigenetic Modifications in Abdominal Aortic Aneurysm Pathogenesis.

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.

A 22-year analysis of the Society for Vascular Surgery Foundation Mentored Research Career Development Award in fostering vascular surgeon-scientists.

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 ∼4 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.

Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2.

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 Mϕs 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.

Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms.

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.

Fenestrated repair improves perioperative outcomes but lacks a hospital volume association for complex abdominal aortic aneurysms.

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.

Epigenetic regulation of the PGE2 pathway modulates macrophage phenotype in normal and pathologic wound repair.

Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-ß-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.

Palmitate-TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing.

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4-/- ) or MyD88 (MyD88-/- ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds.

Epigenetic Regulation of TLR4 in Diabetic Macrophages Modulates Immunometabolism and Wound Repair.

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout (Mll1f/fLyz2Cre+ ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 (Tlr4-/- ) or myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.

Accessing the academic influence of vascular surgeons within the National Institutes of Health iCite database.

OBJECTIVE: A diverse array of measures are used to evaluate academic physicians. One critical factor is the scholarly influence an author has on the research discourse within a field. The National Institutes of Health recently developed the Relative Citation Ratio (RCR) as a method to quantify the influence of published research. The aim of this study was to examine the academic influence of vascular surgeons using RCR within common vascular disease research fields. METHODS: Using the PubMed and National Institutes of Health iCite databases, scientific fields of abdominal and thoracic aortic aneurysm, peripheral artery disease (PAD), cerebral vascular occlusive disease, deep venous thrombosis (DVT), and venous insufficiency were queried for the highest rated RCR articles in each category (2007-2012). To calculate the RCR, article citation rates are divided by an expected citation rate derived from performance of articles in the same field, with the resulting RCR being level and field independent. Article categories were divided into basic science, health services, and clinical research on the basis of two independent reviews. For articles, academic backgrounds of the first, second, and last authors ("influential authors") were collected analyzing procedural specialty: surgery, medicine subspecialty (cardiology, neurology, nephrology), radiology/engineering, and other (anesthesia and pediatrics). Statistical significance between scientific fields and academic background was determined using Student t-test or analysis of variance followed by Newman-Keuls post hoc test. RESULTS: The academic influence of vascular surgeons varied substantially by the scientific field. Vascular surgeons compared with medical specialists were found to have the highest academic influence in abdominal aortic aneurysm research, composing 51% of the influential authors on the highest rated RCR studies (5.9 ± 0.8 vs 5.6 ± 0.8; P = .6). In contrast, vascular surgeons composed only 13% of influential authors compared with medical specialists in DVT (RCR, 2.6 ± 0.3 vs 15.7 ± 1.7; P < .003) and 18% in PAD (RCR, 1.9 ± 0.5 vs 2.1 ± 0.2; P = .78) research fields. Grouping all vascular fields of study together, no difference in RCR was found between vascular surgery and radiology/engineering. However, the mean RCR was significantly lower for vascular surgeons compared with medical subspecialties (4.5 ± 0.4 vs 6.8 ± 0.5; P < .05). CONCLUSIONS: Vascular surgeons exhibit a moderate academic influence in the field of aneurysmal disease but lag behind medical subspecialists in high-impact scientific contributions to the fields of PAD and DVT. Innovative strategies and collaborations are likely needed to increase the influence of vascular surgeons on the academic discourse of several vascular disease research fields.

A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.