Cytokines and the early vein graft: Strategies to enhance durability

This brief review focuses on experimental studies linking the proinflammatory cytokine tumor necrosis factor-α to accelerated vein graft failure in the broader historical context of vein graft research. From some perspectives, the field appears ripe for transfer of cytokine knowledge and therapeutic approaches that have evolved in other systems to vascular surgery problems. However, the complexity of vein graft disease suggests that more robust research approaches, such as broadening of the scope beyond focus on single mediators and neointimal hyperplasia, will be necessary to reach translatable strategies to prolong human vein graft durability

Rationale and practical techniques for mouse models of early vein graft adaptations

Mouse models serve as relatively new yet powerful research tools to study intimal hyperplasia and wall remodeling of vein bypass graft failure. Several model variations have been reported in the past decade. However, the approach demands thoughtful preparation, selected sophisticated equipment, microsurgical technical expertise, advanced tissue processing, and data acquisition. This review compares several described models and aims (building on our personal experiences) to practically aid the investigators who want to utilize mouse models of vein graft failure.Clinical RelevanceSurgical revascularization via vein grafting offers immediate and often dramatic end organ benefit. However, substantial percentages of vein conduits placed develop stenosis or fail, often early. Mechanistic studies of the complex interplay between the biologic and physical forces that drive failure have been hampered by limited quantity and quality of clinical specimens, and the inability of systems such as computer models and cell culture to mimic the clinical circumstance. This review summarizes the power and limitations of mouse vein graft models, and it includes practical experience-based advice for researchers aiming to utilize this tool

Prospective, randomized, multi-institutional clinical trial of a silver alginate dressing to reduce lower extremity vascular surgery wound complications

ObjectiveWound complications negatively affect outcomes of lower extremity arterial reconstruction. By way of an investigator initiated clinical trial, we tested the hypothesis that a silver-eluting alginate topical surgical dressing would lower wound complication rates in patients undergoing open arterial procedures in the lower extremity.MethodsThe study block-randomized 500 patients at three institutions to standard gauze or silver alginate dressings placed over incisions after leg arterial surgery. This original operating room dressing remained until gross soiling, clinical need to remove, or postoperative day 3, whichever was first. Subsequent care was at the provider's discretion. The primary end point was 30-day wound complication incidence generally based on National Surgical Quality Improvement Program guidelines. Demographic, clinical, quality of life, and economic end points were also collected. Wound closure was at the surgeon's discretion.ResultsParticipants (72% male) were 84% white, 45% were diabetic, 41% had critical limb ischemia, and 32% had claudication (with aneurysm, bypass revision, other). The overall 30-day wound complication incidence was 30%, with superficial surgical site infection as the most common. In intent-to-treat analysis, silver alginate had no effect on wound complications. Multivariable analysis showed that Coumadin (Bristol-Myers Squibb, Princeton, NJ; odds ratio [OR], 1.72; 95% confidence interval [CI], 1.03-2.87; P = .03), higher body mass index (OR, 1.05; 95% CI, 1.01-1.09; P = .01), and the use of no conduit/material (OR, 0.12; 95% CI, 0.82-3.59; P < .001) were independently associated with wound complications.ConclusionsThe incidence of wound complications remains high in contemporary open lower extremity arterial surgery. Under the study conditions, a silver-eluting alginate dressing showed no effect on the incidence of wound complications

Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development, Implications for the Treatment of Vein Graft Failure

Objective—Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results—We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage- or endothelial cell (EC)–targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr−/−) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation. Conclusions—These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4–Notch axis as a novel therapeutic target.United States. National Institutes of Health (R01HL107550)American Heart Association (0655878T)American Heart Association (12GRNT9510001)American Heart Association (12GRNT1207025)Good Samaritan FoundationShapiro Family Foundatio

Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1 alpha. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1 alpha. We also identified a requirement for cystathionine-gamma-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.11Ysciescopu

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Fermi Large Area Telescope Observations of Gamma-ray Pulsars PSR J1057-5226, J1709-4429, and J1952+3252

The Fermi Large Area Telescope (LAT) data have confirmed the pulsed emission from all six high-confidence gamma-ray pulsars previously known from the EGRET observations. We report results obtained from the analysis of 13 months of LAT data for three of these pulsars (PSR J1057-5226, PSR J1709-4429, and PSR J1952+3252) each of which had some unique feature among the EGRET pulsars. The excellent sensitivity of LAT allows more detailed analysis of the evolution of the pulse profile with energy and also of the variation of the spectral shape with phase. We measure the cutoff energy of the pulsed emission from these pulsars for the first time and provide a more complete picture of the emission mechanism. The results confirm some, but not all, of the features seen in the EGRET data.Comment: Accepted for publication in ApJ. 45 pages, 12 figures, 11 tables. Corresponding authors: O. Celik, F. Gargano, T. Reposeur, D.J. Thompso

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye