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Substrate stiffness heterogeneities disrupt endothelial barrier integrity in a micropillar model of heterogeneous vascular stiffening.
VanderBurgh JA, Hotchkiss H, Potharazu A, Taufalele PV, Reinhart-King CA
(2018) Integr Biol (Camb) 10: 734-746
MeSH Terms: Adherens Junctions, Animals, Aorta, Atherosclerosis, Cattle, Cell Adhesion, Cell Communication, Cell Movement, Dimethylpolysiloxanes, Endothelial Cells, Endothelium, Vascular, Focal Adhesions, Human Umbilical Vein Endothelial Cells, Humans, Leukocytes, Materials Testing, Neutrophils, Phenotype, Tunica Intima, Vascular Stiffness, Vinculin
Show Abstract · Added April 10, 2019
Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates. We found equivalent disruption of adherens junctions within monolayers on step-rigidity and uniformly stiff substrates relative to uniformly compliant substrates. Similarly, monolayers cultured on step-rigidity substrates exhibited equivalent percentages of leukocyte transmigration to monolayers on rigidity-matched, uniformly stiff substrates. Adherens junction tension and focal adhesion density, but not size, increased within monolayers on step-rigidity and uniformly stiff substrates compared to more compliant substrates suggesting that elevated tension is disrupting adherens junction integrity. Leukocyte transmigration frequency and time, focal adhesion size, and focal adhesion density did not differ between stiff and compliant sub-regions of step-rigidity substrates. Overall, our results suggest that endothelial monolayers exposed to mechanically heterogeneous substrates adopt the phenotype associated with the stiffer matrix, indicating that spatial heterogeneities in intimal stiffness observed with age could disrupt endothelial barrier integrity and contribute to atherogenesis.
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21 MeSH Terms
The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.
VanderBurgh JA, Reinhart-King CA
(2018) Adv Pharmacol 81: 365-391
MeSH Terms: Aging, Animals, Atherosclerosis, Extracellular Matrix, Humans, Tunica Intima, Vascular Remodeling, Vascular Stiffness
Show Abstract · Added April 10, 2019
Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal thickening throughout the arterial tree, fibronectin and collagen deposition, and collagen cross-linking. We then address the most common in vivo and in vitro models used to gain mechanistic insight into the consequences of intimal remodeling. Finally, we consider the impacts of intimal stiffening upon endothelial cell mechanotransduction with emphasis on the emerging impact of increased complexity in cellular traction forces and substrate rigidity upon endothelial barrier integrity.
© 2018 Elsevier Inc. All rights reserved.
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8 MeSH Terms
MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia.
Evans BC, Hocking KM, Osgood MJ, Voskresensky I, Dmowska J, Kilchrist KV, Brophy CM, Duvall CL
(2015) Sci Transl Med 7: 291ra95
MeSH Terms: Animals, Endocytosis, Endosomes, Humans, Hyperplasia, Intracellular Signaling Peptides and Proteins, Lysosomes, Male, Myocytes, Smooth Muscle, Nanoparticles, Peptides, Phenotype, Phosphorylation, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Rabbits, Saphenous Vein, Treatment Outcome, Tunica Intima, Vascular Grafting
Show Abstract · Added March 14, 2018
Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen-activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i-NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure.
Copyright © 2015, American Association for the Advancement of Science.
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1 Members
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20 MeSH Terms
Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.
Milstone DS, Ilyama M, Chen M, O'Donnell P, Davis VM, Plutzky J, Brown JD, Haldar SM, Siu A, Lau AC, Zhu SN, Basheer MF, Collins T, Jongstra-Bilen J, Cybulsky MI
(2015) Circ Res 117: 166-77
MeSH Terms: 5' Untranslated Regions, Animals, Atherosclerosis, Carotid Artery Injuries, Cells, Cultured, Chemotaxis, Leukocyte, Cholesterol, Dietary, E-Selectin, Endothelial Cells, Endothelium, Vascular, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Interaction Mapping, RNA Polymerase II, Receptors, LDL, Response Elements, Transcription Factor RelA, Transcription, Genetic, Tunica Intima, Vascular Cell Adhesion Molecule-1
Show Abstract · Added September 6, 2016
RATIONALE - Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.
OBJECTIVE - Determine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene.
METHODS AND RESULTS - Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.
CONCLUSIONS - This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
© 2015 American Heart Association, Inc.
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23 MeSH Terms
Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice.
Sun X, He S, Wara AKM, Icli B, Shvartz E, Tesmenitsky Y, Belkin N, Li D, Blackwell TS, Sukhova GK, Croce K, Feinberg MW
(2014) Circ Res 114: 32-40
MeSH Terms: Animals, Aorta, Apolipoproteins E, Atherosclerosis, CD4-Positive T-Lymphocytes, Diet, High-Fat, Human Umbilical Vein Endothelial Cells, Humans, Inflammation, Karyopherins, Macrophages, Mice, Mice, Inbred C57BL, MicroRNAs, NF-kappa B, Tunica Intima
Show Abstract · Added March 7, 2014
RATIONALE - Activated nuclear factor (NF)-κB signaling in the vascular endothelium promotes the initiation and progression of atherosclerosis. Targeting endothelial NF-κB may provide a novel strategy to limit chronic inflammation.
OBJECTIVE - To examine the role of microRNA-181b (miR-181b) in endothelial NF-κB signaling and effects on atherosclerosis.
METHODS AND RESULTS - MiR-181b expression was reduced in the aortic intima and plasma in apolipoprotein E-deficient mice fed a high-fat diet. Correspondingly, circulating miR-181b in the plasma was markedly reduced in human subjects with coronary artery disease. Systemic delivery of miR-181b resulted in a 2.3-fold overexpression of miR-181b in the aortic intima of apolipoprotein E-deficient mice and suppressed NF-κB signaling revealed by bioluminescence imaging and reduced target gene expression in the aortic arch in apolipoprotein E-deficient/NF-κB-luciferase transgenic mice. MiR-181b significantly inhibited atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4+ T cells in the vessel wall. Mechanistically, miR-181b inhibited the expression of the target gene importin-α3, an effect that reduced NF-κB nuclear translocation specifically in the vascular endothelium of lesions, whereas surprisingly leukocyte NF-κB signaling was unaffected despite a 7-fold overexpression of miR-181b. Our findings uncover that NF-κB nuclear translocation in leukocytes does not involve importin-α3, but rather importin-α5, which miR-181b does not target, highlighting that inhibition of NF-κB signaling in the endothelium is sufficient to mediate miR-181b's protective effects.
CONCLUSIONS - Systemic delivery of miR-181b inhibits the activation of NF-κB and atherosclerosis through cell-specific mechanisms in the vascular endothelium. These findings support the rationale that delivery of miR-181b may provide a novel therapeutic approach to treat chronic inflammatory diseases such as atherosclerosis.
1 Communities
1 Members
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16 MeSH Terms
Surgical vein graft preparation promotes cellular dysfunction, oxidative stress, and intimal hyperplasia in human saphenous vein.
Osgood MJ, Hocking KM, Voskresensky IV, Li FD, Komalavilas P, Cheung-Flynn J, Brophy CM
(2014) J Vasc Surg 60: 202-11
MeSH Terms: Aged, Endothelium, Vascular, Female, Humans, Hydrogen Peroxide, Hyperplasia, Male, Middle Aged, Muscle, Smooth, Vascular, Nitric Oxide Synthase, Organ Culture Techniques, Oxidative Stress, Platelet Endothelial Cell Adhesion Molecule-1, Reactive Oxygen Species, Saphenous Vein, Time Factors, Tunica Intima, Vascular Surgical Procedures, Warm Ischemia
Show Abstract · Added March 9, 2015
INTRODUCTION - Human saphenous vein (HSV) is the most widely used bypass conduit for peripheral and coronary vascular reconstructions. However, outcomes are limited by a high rate of intimal hyperplasia (IH). HSV undergoes a series of ex vivo surgical manipulations prior to implantation, including hydrostatic distension, marking, and warm ischemia in solution. We investigated the impact of surgical preparation on HSV cellular function and development of IH in organ culture. We hypothesized that oxidative stress is a mediator of HSV dysfunction.
METHODS - HSV was collected from patients undergoing vascular bypass before and after surgical preparation. Smooth muscle and endothelial function were measured using a muscle bath. Endothelial preservation was assessed with immunohistochemical staining. An organ culture model was used to investigate the influence of surgical preparation injury on the development of IH. Superoxide levels were measured using a high-performance liquid chromatography-based assay. The influence of oxidative stress on HSV physiologic responses was investigated by exposing HSV to hydrogen peroxide (H2O2).
RESULTS - Surgical vein graft preparation resulted in smooth muscle and endothelial dysfunction, endothelial denudation, diminished endothelial nitric oxide synthase staining, development of increased IH, and increased levels of reactive oxygen species. Experimental induction of oxidative stress in unmanipulated HSV by treatment with H2O2 promoted endothelial dysfunction. Duration of storage time in solution did not contribute to smooth muscle or endothelial dysfunction.
CONCLUSIONS - Surgical vein graft preparation causes dysfunction of the smooth muscle and endothelium, endothelial denudation, reduced endothelial nitric oxide synthase expression, and promotes IH in organ culture. Moreover, increased levels of reactive oxygen species are produced and may promote further vein graft dysfunction. These results argue for less injurious means of preparing HSV prior to autologous transplantation into the arterial circulation.
Copyright © 2014 Society for Vascular Surgery. All rights reserved.
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2 Members
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19 MeSH Terms
Variants in adiponectin signaling pathway genes show little association with subclinical CVD in the diabetes heart study.
Cox AJ, Lambird JE, An SS, Register TC, Langefeld CD, Carr JJ, Freedman BI, Bowden DW
(2013) Obesity (Silver Spring) 21: E456-62
MeSH Terms: Adaptor Proteins, Signal Transducing, Adiponectin, Aged, Cardiovascular Diseases, Diabetes Complications, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genotype, Humans, Inflammation, Lipids, Male, Middle Aged, Muramidase, Obesity, Phenotype, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Receptors, Adiponectin, Signal Transduction, Tunica Intima, Tunica Media, Vascular Calcification
Show Abstract · Added February 15, 2014
OBJECTIVE - Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM.
DESIGN AND METHODS - Single-nucleotide polymorphisms (SNPs) in ADIPOQ (n = 45), SNPs tagging ADIPOR1 (n = 6), APIPOR2 (n = 8), APPL1 (n = 6) and known rare coding variants in KNG1 (n = 3) and LYZL1 (n = 3) were genotyped in 1220 European Americans from the family-based Diabetes Heart Study. Associations between SNPs and phenotypes of interest were assessed using a variance components analysis with adjustment for age, sex, T2DM-affected status, and body mass index.
RESULTS - There was minimal evidence of association between SNPs in the adiponectin signaling pathway genes and measures of calcified plaque; eight of the 71 SNPs showed evidence of association with subclinical CVD (P = 0.007-0.046) but not with other phenotypes examined. Nine additional SNPs were associated with at least one of the plasma lipid measures (P = 0.008-0.05).
CONCLUSION - Findings from this study do not support a significant role for variants in the adiponectin signaling pathway genes in contributing to risk for vascular calcification in T2DM. However, further understanding the interplay between adiposity, plasma lipids, and inflammation may prove important in the prediction and management of cardiovascular complications in T2DM.
Copyright © 2012 The Obesity Society.
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1 Members
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24 MeSH Terms
Intimal thickness associated with endothelial dysfunction in human vein grafts.
Li FD, Sexton KW, Hocking KM, Osgood MJ, Eagle S, Cheung-Flynn J, Brophy CM, Komalavilas P
(2013) J Surg Res 180: e55-62
MeSH Terms: Endothelium, Vascular, Humans, Hyperplasia, Organ Culture Techniques, Saphenous Vein, Tunica Intima, Vasodilation
Show Abstract · Added March 9, 2015
BACKGROUND - Intimal hyperplasia is a complex process thought to be initiated by injury and is the leading cause of vein graft failure. In the present investigation, we hypothesized that the basal intimal thickness in the human saphenous vein is a predictor of endothelial dysfunction and, potentially, intimal hyperplasia.
METHODS - Human saphenous veins were obtained during coronary artery bypass surgery. The segments were contracted with phenylephrine and relaxed with carbachol to determine the endothelial-dependent relaxation. The vein segments were fixed in 10% buffered formalin and grown for 14 d in high-serum culture and then fixed in formalin. The fixed tissues were stained with Verhoeff-Van Gieson, and the average intimal and medial thicknesses were calculated using light microscopy and a computerized image analysis system.
RESULTS - The human saphenous veins displayed varying amounts of basal intimal thickness (range 18.80-241.3 μm). The endothelial-dependent relaxation of the veins was highly variable, with values ranging from 0% to 27.59%. Human saphenous veins with a basal intimal thickness greater than 120 μm had significantly less endothelial-dependent relaxation (8.90% ± 6.32%) than those with a basal intimal thickness less than 120 μm (21.97% ± 10.64%). Endothelial dysfunction correlated with a basal intimal thickness greater than 120 μm (P = 0.02). The basal intimal thickness also correlated with increased intimal thickness after 14 d in organ culture (P = 0.0001).
CONCLUSIONS - A basal intimal thickness greater than 120 μm is a predictor of endothelial dysfunction. Also, because a greater basal intimal thickness correlated with an increased intimal thickness after organ culture, the basal intimal thickness might predict vein graft failure owing to intimal hyperplasia.
Published by Elsevier Inc.
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2 Members
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7 MeSH Terms
Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo.
Muto A, Panitch A, Kim N, Park K, Komalavilas P, Brophy CM, Dardik A
(2012) Vascul Pharmacol 56: 47-55
MeSH Terms: Amino Acid Sequence, Animals, Anti-Inflammatory Agents, Cell Proliferation, Cells, Cultured, Endothelial Cells, Fibrosis, Graft Occlusion, Vascular, Humans, Hyperplasia, Interleukin-6, Interleukin-8, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Myocytes, Smooth Muscle, Nitroprusside, Peptides, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Saphenous Vein, Tunica Intima, Vasodilation
Show Abstract · Added March 9, 2015
Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeant peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.
Published by Elsevier Inc.
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23 MeSH Terms
A novel cell permeant peptide inhibitor of MAPKAP kinase II inhibits intimal hyperplasia in a human saphenous vein organ culture model.
Lopes LB, Brophy CM, Flynn CR, Yi Z, Bowen BP, Smoke C, Seal B, Panitch A, Komalavilas P
(2010) J Vasc Surg 52: 1596-607
MeSH Terms: Animals, Aorta, Arsenites, Cell Movement, Cells, Cultured, Collagen, Connective Tissue Growth Factor, Enzyme Inhibitors, Fibronectins, HSP27 Heat-Shock Proteins, Humans, Hyperplasia, Intracellular Signaling Peptides and Proteins, Lysophospholipids, Microscopy, Confocal, Muscle, Smooth, Vascular, Peptides, Phosphorylation, Protein Array Analysis, Protein-Serine-Threonine Kinases, Rats, Saphenous Vein, Sodium Compounds, Tissue Culture Techniques, Tunica Intima, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 9, 2015
OBJECTIVE - The present study was aimed at developing a new cell-permeant peptide inhibitor (MK2i) of the kinase that phosphorylates and activates heat-shock protein (HSP)27 (MAPKAP kinase II), and evaluating the ability of this peptide to inhibit HSP27 phosphorylation and intimal thickening.
METHODS - The ability of MK2i to reduce HSP27 phosphorylation and cell migration was evaluated in A7R5 cells stimulated with arsenite or lysophosphatidic acid. Stable isotopic labeling using amino acids in cell culture, in combination with liquid chromatography mass spectrometry, was used to characterize the effect of MK2i on global protein expression in fibroblasts. The effect of MK2i on intimal thickening and connective tissue growth factor expression was evaluated in human saphenous vein (HSV) rings maintained with 30% fetal bovine serum for 14 days by light microscopy and immunoblotting.
RESULTS - Pretreatment of cells with MK2i (10 μM) prior to arsenite or lysophosphatidic acid stimulation decreased phosphorylation of HSP27 (36% ± 9% and 33% ± 10%, respectively) compared with control (not pretreated) cells. MK2i also inhibited A7R5 migration, and downregulated the transforming growth factor-induced expression of collagen and fibronectin in keloid cells, two major matrix proteins involved in the development of intimal hyperplasia. Treatment of HSV segments with MK2i enhanced relaxation, reduced HSP27 phosphorylation (40% ± 17%), connective tissue growth factor expression (17% ± 5%), and intimal thickness (48.2% ± 10.5%) compared with untreated segments. On the other hand, treatment with a recombinant fusion protein containing a cell-permeant peptide attached to the HSP27 sequence increased intimal thickness of HSV segments by 48% ± 14%.
CONCLUSION - Our results suggest that HSP27 may play a role in the development of processes leading to intimal hyperplasia in HSV, and reduction of HSP27 phosphorylation by MK2i may be a potential strategy to inhibit the development of intimal hyperplasia in HSV to prevent the autologous vascular graft failure.
Published by Mosby, Inc.
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26 MeSH Terms