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PubMed2005

Combined use of brachial-ankle pulse wave velocity and ankle-brachial index for fast assessment of arteriosclerosis and atherosclerosis in a community.

BACKGROUND: Pulse volume recordings and blood pressures at arms and ankles can be obtained automatically and simultaneously to allow fast measurements of the brachial-ankle pulse wave velocity and the ankle-brachial index. We applied this novel technique to assess the extent of arteriosclerosis and atherosclerosis in a community. METHODS: A total of 1329 residents in Kinmen completed a health survey including interview, physical examination, blood test, and the measurements of brachial-ankle pulse wave velocity and ankle-brachial index in 10 working days. RESULTS: Brachial-ankle pulse wave velocity was significantly related to age, systolic blood pressure, body mass index, waist circumference, ankle-brachial index, and fasting blood levels of glucose, triglyceride, high-density lipoprotein cholesterol, uric acid, and creatinine, and was significantly related to the 10-year risk of developing coronary heart disease estimated from the Framingham risk function. The prevalence of arteriosclerosis as defined by brachial-ankle pulse wave velocity values higher than the age and sex stratified references from the low risk subjects was 27.1% for men and 25.4% for women. The prevalence of atherosclerosis defined by ankle-brachial index <0.9 was 2.8% in men and 1.7% in women. In men but not in women, subjects with low ankle-brachial index had significantly greater risk for developing coronary artery disease than those with normal values. CONCLUSIONS: Brachial-ankle pulse wave velocity and ankle-brachial index can be obtained simultaneously and quickly for the assessment of arteriosclerosis and atherosclerosis in a community.

Adult↗
PubMedDate not supplied

Prolonged cold preservation promotes the recipient's cell participating in neointima formation but delays the later graft arteriosclerosis in rat model.

Chronic graft dysfunction is the greatest barrier to long-term graft survival, although the immediate outcome in organ transplantation has been greatly improved. Graft arteriosclerosis is a prominent feature of chronic graft dysfunction. Recipient progenitor cells have been shown to participate in neointimal development in graft arteriosclerosis. The present study investigated the role of recipient endothelial cells in the repair and remodeling after a cold preservation injury in an orthotopic cross-sex abdominal aortic allotransplantation model, namely female Wistar to male Sprague-Dawley rats. Grafts were preserved for 48 hours in 4 degrees C University of Wisconsin (UW) solution for a prolonged cold ischemia (PCI) group or preserved for <1 hour in the control group; or for <1 hour in the presence of feeding with cyclosporine (CyA). A direct in situ polymerase chain reaction (ISPCR) for the SRY gene showed SRY-marked endothelial and smooth muscle-like cells in neointima at 2 weeks in the PCI group, at 4 weeks in the control group, and rarely at 3 months in the CyA group. Staining by H&E showed the aortic graft intima to be thicker in the PCI than in the control group at 4 weeks, but thinning thereafter. The SRY-positive cells correlated with intimal thickness in the PCI and the control group (r = .801 and .825; P < .05 and <.05, respectively), but not in the CyA group (r = .247, P > .5). Our data suggest that prolonged cold preservation promotes recipient cell participation in graft arteriosclerosis after endothelium injury. The early neointimal formation via recipient cells incorporated into arteriosclerotic neointima may delay later intimal thickening. In the aortic allotransplantation model, prolonged cold ischemia may be beneficial for long-term graft survival due to early endothelial replacement. We hypothesize that controlled injury to the graft may serve as a new strategy for treatment of intimal thickening.

Animals↗
PubMed2001

Candesartan cilexetil reduces graft arteriosclerosis in aortic transplantation model in rat.

To date established treatment of transplant arteriosclerosis is basically missing and there is a need for new therapeutic approaches. Angiotensin II (Ang II) and Ang II receptor type 1 (AT) are present in the vascular wall. Blocking of the AT1 receptor by pharmacological agents may inhibit damaging effects of Ang II on endothelial and smooth muscle cells. The purpose of the study was to evaluate the effect of the AT1 receptor blocker Candesartan cilexetil on the development of graft arteriosclerosis in a rat aortic transplant model. Two strain combinations were used for aortic transplantation: DA to PVG; and PVG to PVG. The animals received Candesartan cilexetil treatment (9.5 + 1.4 mg/kg/day) for 8 weeks. Candesartan cilexetil treatment reduced neointimal formation both in allografts (Qint 30.2 +/- 8.8% vs. 22.1 +/- 8.7%, P < 0.05) and in isografts (Qint 15.5 +/- 4.4% vs. 6.7 +/- 3.3%, P = 0.0001). Blocking of the AT1 receptor signalling by Candesartan cilexetil was also associated with a reduced expression of TGF-beta1. Macrophage infiltration was not affected by the treatment. Candesartan cilexetil treatment leads to reduced neointimal formation in aortic transplant. The positive effect of the drug might be partly explained by a reduction of TGF-beta1 expression in the grafts. Candesartan treatment may provide another possibility for prevention of transplant arteriosclerosis and chronic rejection.

Animals↗
PubMedDate not supplied

Effect of low-density lipoprotein apheresis on plasma endothelin-1 levels in diabetic hemodialysis patients with arteriosclerosis obliterans.

Endothelin (ET)-1 has been implicated in the pathogenesis of diabetes, arteriosclerosis, and chronic renal failure. We studied whether low-density lipoprotein (LDL) apheresis alters plasma ET-1 levels in diabetic hemodialysis patients with arteriosclerosis obliterans (ASO). Plasma ET-1 levels were measured in 30 healthy control subjects (Group A), 30 diabetes patients without ASO (Group B), 20 diabetes patients with ASO (Group C), 20 diabetes patients without ASO who were undergoing hemodialysis (Group D), and 6 diabetes patients with ASO who were undergoing hemodialysis (Group E). Hemodialysis patients were dialyzed three times weekly with a bicarbonate dialysate. Six diabetic hemodialysis patients with ASO underwent LDL apheresis once weekly for 10 weeks, and the change in plasma ET-1 levels due to LDL apheresis was measured. LDL apheresis resulted in a statistically significant decrease in levels of total cholesterol and LDL cholesterol. In addition, LDL apheresis improved clinical symptoms in all patients. Plasma ET-1 levels in Group E (15.0+/-1.9 pg/ml) were significantly higher than those in Groups A (1.0+/-0.6 pg/ml, P<.001), B (1.3+/-0.5 pg/ml, P<.001), C (5.6+/-1.0 pg/ml, P<.001), and D (10.4+/-1.6 pg/ml, P<.01). Plasma ET-1 levels decreased progressively and significantly after a single LDL apheresis began (9.4+/-1.0 pg/ml after 60 min, P<.001, and 6.0+/-1.0 pg/ml after 120 min, P<.001). These data suggest that ET-1 may be associated with arteriosclerosis and that LDL apheresis enhances peripheral microcirculation in part by reducing the production of ET-1 in diabetic hemodialysis patients with ASO.

Adult↗
PubMed2006

Prevalence of arteriosclerosis and atherosclerosis in stable patients at a cardiovascular outpatient clinic: potential for better care.

BACKGROUND: Cardiovascular treatment guidelines for stable patients who are regularly followed up at medical center clinics have long been practiced and are intended to improve arteriosclerosis and atherosclerosis in these patients. The present study investigated the prevalence of arteriosclerosis and atherosclerosis in patients attending one such clinic, and explored the potential for better care. METHODS: A total of 124 outpatients randomly selected from 586 stable outpatients on regular visits to the same senior cardiologist were invited to receive measurements of brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) using a novel device during their clinic visits. Abnormally high baPWV was defined using the age- and sex-stratified reference ranges obtained from a previous community survey. RESULTS: The prevalence of high baPWV in the studied outpatients was 24.2% and the prevalence of low ABI (< 0.9) was 8.1%. Based on the reports of baPWV and ABI at the point of care, medications were adjusted in 56 patients (45.2%). In 22 patients who had adjusted antihypertensive medication and repeat examinations of baPWV and ABI at subsequent visits, systolic blood pressure fell by 11 mmHg (p = 0.012), and baPWV fell by 0.2 m/s (p = 0.001). CONCLUSION: Abnormal baPWV and ABI are not uncommon in stable patients who are regularly followed up at a cardiology clinic where treatment guidelines are completely followed. Fast assessment of arteriosclerosis and atherosclerosis at the point of care may provide better care for this group of patients.

Adult↗
PubMed1998

Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes.

We investigated the pathogenesis of chronic allograft rejection in mouse cardiac allografts. Long-term survival occurred after administration of monoclonal antibody to CD4 or CD40-ligand (CD40L) plus donor cells. Both treatments induced permanent graft survival, but, in contrast to transplants in mice treated with CD4 monoclonal antibody, grafts in mice treated with CD40L monoclonal antibody lacked evidence of chronic rejection, including transplant arteriosclerosis. Freedom from chronic rejection in the group treated with CD40L monoclonal antibody correlated with vascular expression of the 'protective' genes heme oxygenase-1 (HO-1), Bcl-xL and A20. Moreover, arteriosclerosis was induced in allografts in immunoglobulin-deficient mice by antibody transfer only when the transfer was done before expression of protective genes. A direct role for protective gene expression in endothelial cells was demonstrated by in vitro experiments in which induction of HO-1 or Bcl-xL suppressed alloantibody-stimulated endothelial activation. Finally, induction of HO-1 in vivo protected allografts against chronic injury. These data show a role for protective genes in the prevention of chronic rejection, and indicate new approaches to protect grafts against development of transplant arteriosclerosis.

Animals↗
PubMed2003

Mouse endothelial CD40 expression does not play a role during the development of transplant arteriosclerosis.

Endothelial cells (ECs) are of major interest in allograft rejection. The authors and others have recently shown in different mouse allograft models that, during the development of transplant arteriosclerosis, donor ECs are replaced by recipient ECs. It was the aim of this study to characterize the phenotype of ECs during the development of transplant arteriosclerosis further, with particular interest in their capability to express CD40. Abdominal aortic allografts were transplanted across a full major histocompatibility complex (MHC) barrier using BALB/c (H-2d) mice as donors and C57BL/6 (H-2b) mice as transplant recipients. Aortic allografts were harvested on days 7 and 30 after transplantation and analyzed by double-immunohistochemistry for expression of CD40 and CD31. As the authors have previously shown that ECs in the aortic allograft model are of donor origin on day 7 after transplantation, whereas by day 30 donor ECs have been replaced by ECs of recipient origin, these two time points were chosen for analysis of CD40 expression. Double-immunohistochemistry for CD40 and CD31 revealed no endothelial expression of CD40 at either time point. These initial results obtained with the anti-CD40 monoclonal antibody (mAb) (clone 3/23) were confirmed by two further experiments using two different anti-CD40 mAbs (clone HM40-3 and clone 1/10) that bind to epitopes of the CD40 receptor distinct to that of 3/23. Neither mAb revealed endothelial expression of CD40. Further analysis of the composition of the cellular infiltrate demonstrated that the majority of macrophages were CD40 positive. The data indicate that in this mouse model of aortic transplantation, neither recipient- nor donor-derived ECs express CD40 during the development of transplant arteriosclerosis. Therefore, in contrast to rat or human ECs, CD40 expression by mouse ECs does not seem to play a major role in this form of allograft rejection.

Animals↗
PubMed2003

Which parameter is more influential on the development of arteriosclerosis in hemodialysis patients?

Arteriosclerosis is characterized by stiffening of arteries. The incremental elastic modulus (Einc) measurement is a good marker of arterial wall stiffness. Metabolic, inflammatory and hemodynamic alterations cause structural changes and vascular complications in end stage renal disease. The aim of the present study was to evaluate the factors that may affect the development of arteriosclerosis by measurement of Einc in hemodialysis (HD) patients. Thirty-two patients (16 men; 16 female) on chronic HD with a mean age of 42.2 +/- 19.3 (range: 15-80) were included in the study. The carotid Einc was measured to determine arteriosclerosis by high-resolution echo-tracking system (Acuson Aspen, Acuson Corp., Mountain View, California, USA). Einc measurement was calculated from transcutaneous measurements of common carotid arterial (CCA) internal diameter and wall thickness and carotid pulse pressure. Common carotid compliance and distensibility were determined from changes in carotid artery diameter during systole and simultaneously measured carotid pulse pressure. Common carotid artery stuffiness (Einc) was influenced by age, systolic blood pressure (SBP), pulse pressure (PP), calcium (Ca) and alkaline phosphatase (ALP). The distensibility of CCA was correlated with age, SBP, diastolic blood pressure (DBP), PP, Ca, ALP, and parathormone (PTH). The inflammatory parameter, hs-CRP, was increased with Einc. The mean Einc measurement was found significantly increased in patient receiving vitamin D. In conclusion, the stiffening of carotid artery in HD patients is related not only to hemodynamic changes (increased SBP, PP) but also to metabolic (increased Ca) and to inflammation (increased hs-CRP). Carotid Einc is accepted independent risk factor for cardiovascular mortality. Because of the positive correlation between Einc and serum Ca, vitamin D and Ca containing phosphorus (P) binders should be used carefully.

Adolescent↗
PubMed1956

Does the ingestion of alcohol influence the development of arteriosclerosis in fowls?

The effect of alcohol ingestion upon the development of naturally occurring and stilbestrol-induced arteriosclerosis was studied in the domestic fowl. In two experiments, a 15 per cent ethyl alcohol solution was used for drinking purposes, and in a third experiment wine containing 12 per cent of it was administered. The caloric intake of both food and alcohol was carefully controlled by pair-feeding, a glucose solution being used for drinking purposes to equalize the caloric intakes of the control birds with those of the alcohol-treated birds. A total of 224 cockrels was studied, and the period of observation for each experiment lasted 12 months. The degree of arteriosclerosis in the thoracic and abdominal aortas was determined in the gross and microscopically, and the degree of lipide infiltration was determined microscopically. The gross grading of arteriosclerotic lesions agreed closely with the microscopic analysis of intimal thickening and lipide infiltration of the arterial wall. The gross gradings were subjected to a critical statistical analysis which allowed precise statements to be made on the probability that a real effect would be overlooked. This analysis yielded no evidence that alcohol or the wine used had affected the degree of gross arteriosclerosis or lipide infiltration.

Alcohol Drinking↗
PubMed1993

Somatostatin analog lanreotide inhibits myocyte replication and several growth factors in allograft arteriosclerosis.

Chronic rejection is the most common reason for late loss of a transplant. The molecular mechanism of chronic rejection is not known and there is no treatment for this disorder. The characteristic histological feature in chronic rejection is increased smooth muscle cell replication in the vascular wall, leading to allograft arteriosclerosis. In this study we demonstrate that nonimmunosuppressed rat aortic allografts undergoing chronic rejection synthesize increased quantities of several smooth muscle cell growth-promoting substances in the vascular wall including interleukin-1, eicosanoids, and several peptide growth factors. Administration of a stable somatostatin analog lanreotide, BIM 23014, strongly inhibits myocyte proliferation in the allograft in vivo. It has no inhibitory effect on the proliferation of smooth muscle cells in vitro. Concomitantly, the locally produced peptide growth factors, i.e., epidermal growth factor, insulin-like growth factor 1, and BB-isomer of platelet-derived growth factor, but not other mediators of inflammation, are significantly reduced. The results suggest that growth factors are the main effector molecules leading to myocyte proliferation in allograft arteriosclerosis and that allograft arteriosclerosis (chronic rejection) may be specifically inhibited by lanreotide administration.

Animals↗
PubMed1996

Presensitization accelerates allograft arteriosclerosis.

Transplant arteriosclerosis is the major factor influencing allograft survival after the first year posttransplantation. The host's immunologic response is one of the principal effectors responsible for the constitution of this vascular wall lesion, but the effector pathway and the factors influencing the immune injury are not clear. In a rat abdominal aortic allograft model, we used a skin priming method to study the influence of sensitization on the occurrence of vascular wall lesions. Primed rats developed transplant arteriosclerosis lesions involving medial decellularization and intimal proliferation before the 21st day, whereas naive animals had the same lesions at 2 months posttransplantation. A significant difference between primed and naive rats was found for medial thickness (48.00 +/- 2.85 microm versus 79.34 +/- 2.55 microm, P<0.001) and smooth muscle cell content (160 +/- 28 cell/mm versus 466 +/- 19 cell/mm, P<0.001) at 21 days posttransplantation, and intimal hyperplasia was seen in primed animals at that time, whereas it was not observed in naive rats until the 60th day. The immune profile in naive and primed animals was different. The immune cells infiltrating the arterial wall in naive rats, were principally macrophages and CD8+ T-lymphocytes. No Ig or complement deposition was detected. IgG and complement activated fraction were present in the media of primed animals as early as the fifth day posttransplantation and CD4+ T lymphocytes were the dominant immune cell population. In conclusion, sensitization influences the immune mechanisms responsible for the development of transplant arteriosclerosis and alters the rate of its evolution.

Animals↗
PubMed1997

Synthetic MHC class I peptide prolongs cardiac survival and attenuates transplant arteriosclerosis in the Lewis-->Fischer 344 model of chronic allograft rejection.

BACKGROUND: A synthetic peptide corresponding to residues 75-84 of the alpha1 domain of HLA-B7 molecule (HLA-B7.75-84 [Allotrap]) inhibits cytotoxic T cell function in vitro and, when combined with subtherapeutic doses of cyclosporine (CsA), prolongs allogeneic cardiac survival. We now report the effects of HLA-B7.75-84 in the Lewis --> Fischer 344 rat model of chronic cardiac allograft rejection. METHODS: Animals were treated with CsA (5 mg/kg/day s.c.) alone or with CsA plus alternate-day HLA-B7.75-84 (20 mg/kg/day i.p.) for 30 days. Allografts harvested at day 100 were evaluated by histology and immunohistology. RESULTS: HLA-B7.75-84 plus CsA prolonged allograft survival (75% of allografts survived >90 days) compared with CsA alone (27% of allografts survived >90 days) (P<0.05). Histologic examination of control allografts showed dense cellular infiltrates and moderate transplant arteriosclerosis (>75% of arteries showed 10-20% occlusion). Infiltrating leukocytes consisted of macrophages (>75% cells), T cells (10-20%), and rare natural killer cells (<5%). Cell activation was shown by expression of major histocompatibility complex class II antigens (>75%), interleukin (IL) 2 receptor (5-10%), and staining for IL-2 (approximately 5% of intragraft mononuclear cells), interferon-gamma (5-10%) and tumor necrosis factor-alpha (approximately 20%). Leukocytes and vessels also showed labeling for the fibrogenic cytokine, transforming growth factor-beta, and all vessels showed dense deposition of IgG (IgG2a, IgG2b) and C3. The addition of HLA-B7.75-84 decreased overall cellularity (P<0.01) without affecting the composition of the infiltrate, but completely prevented transplant arteriosclerosis, diminished myocardial injury, and abrogated expression of IL-2R, IL-2, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta. HLA-B7.75-84 also blunted the humoral response, which resulted in a predominance of vascular deposition of the non-complement-fixing IgG2c isotype and a concomitant decrease in C3. CONCLUSIONS: Therapy with synthetic class I major histocompatibility complex peptide (HLA-B7.75-84) attenuates key histologic features of graft arteriosclerosis, in association with inhibition of multiple cytokines and growth factors and modulation of host alloantibody responses in vivo, which is of interest since Allotrap is currently undergoing clinical trials.

Animals↗
PubMed2000

Endothelial nitric oxide synthase protects aortic allografts from the development of transplant arteriosclerosis.

BACKGROUND: Inducible nitric oxide synthase (iNOS) is up-regulated in rejecting allografts and is protective against allograft arteriosclerosis; it suppresses neointimal smooth muscle cell accumulation and inhibits adhesion of platelets and leukocytes to the endothelium. However, the functional importance of endothelial NOS (eNOS) in the rejecting allografts remains unclear. METHODS: We examined the effects of selective eNOS deficiency in aortic allografts in a murine chronic rejection model using grafts from eNOS knockout (KO) mice (C57BL/6 background; H2b) and normal C3H (H2K) as recipients. Grafts from wild-type C57BL/6 mice served as controls. Grafts from iNOS KO mice served as a second group of controls where the contribution from iNOS was eliminated but eNOS was preserved. Aortic grafts were harvested and analyzed at days 10-14, 18-22, and 26-30 after transplantation. RESULTS: Endothelial NOS-deficient grafts showed significantly increased intima/media ratios at days 26-30 compared to controls. Immunostaining demonstrated that in eNOS KO grafts, eNOS was not detectable whereas iNOS was expressed prominently in infiltrating recipient mononuclear cells. In control grafts, eNOS expression was preserved in the endothelium even by day 30, and associated with a decrease in intimal thickening. We further demonstrated that early overexpression of iNOS by ex vivo gene transfer completely prevented the development of arteriosclerosis associated with eNOS deficiency. CONCLUSIONS: We found that eNOS plays a protective role in allografts, and that in eNOS-deficient allografts, early overexpression of iNOS is capable of preventing the development of allograft arteriosclerosis. In allografts with dysfunctional vascular endothelium and impaired eNOS activity as a result of ischemia or native arteriosclerotic disease, iNOS gene therapy may serve to improve their long-term survival and function.

Animals↗
PubMed2000

CD8+ T cells contribute to the development of transplant arteriosclerosis despite CD154 blockade.

BACKGROUND: The CD40-CD154 receptor-ligand pair plays a critical role in allograft rejection by mediating the activation of endothelial cells, antigen-presenting cells, and T cells. Blockade of this interaction prevents acute allograft rejection and leads to prolonged allograft survival in numerous experimental models, but in most cases indefinite graft survival is not achieved due to evolving transplant arteriosclerosis. In this study, we have used a model of transplant arteriosclerosis to investigate whether CD4+ and CD8+ T cells are differentially affected by CD154 blockade. METHODS: BALB/c (H2d) aortic grafts were transplanted into C57BL/6 (H2b) recipients treated with anti-CD154 monoclonal antibody in the presence or absence of CD8+ T-cell depletion. Histology and morphometric measurements were performed on day 30 after transplantation. RESULTS: Only combined treatment with anti-CD154 and anti-CD8 monoclonal antibodies resulted in a significant reduction of intimal proliferation (33 +/-10% vs. 67+/-14%; untreated control). Administration of either antibody alone did not produce this effect. Thymectomy did not alter the degree of intimal proliferation observed in any of the treatment groups. CONCLUSIONS: Our data provide direct evidence that CD8+ T cells are not targeted effectively by CD154 blockade and that the transplant arteriosclerosis seen after CD154 blockade is not due to recent thymic emigrant T cells.

Animals↗
PubMed2002

Platelet-endothelial cell adhesion molecule-1 (CD31) expression on donor endothelial cells attenuates the development of transplant arteriosclerosis.

BACKGROUND: Platelet-endothelial cell adhesion molecule(PECAM)-1 (CD31) is expressed on the surface of endothelial cells, platelets, monocytes, neutrophils, and certain T-cell subsets. Treatment of endothelial cells with anti-PECAM-1 antibody inhibits leukocyte transmigration. This study was designed to test the hypothesis that, in transplantation, the absence of PECAM-1 expression on donor endothelial cells would reduce the number of leukocytes transmigrating into the allograft, thereby attenuating the development of transplant arteriosclerosis. METHODS: PECAM-1 and PECAM (C57BL/6/H2 ) abdominal aortic allografts were transplanted into BALB/c (H2 ) recipients; syngeneic grafts were used as controls. Aortic grafts were analyzed by performing morphometry, immunohistochemistry, and quantitative reverse transcriptase-polymerase chain reaction for the detection of intragraft cytokine mRNA production. RESULTS: Intimal proliferation was exacerbated in PECAM-1 grafts (57+/-5% for PECAM-1 vs. 36+/-6% for PECAM-1; <0.005; n=6). The absence of PECAM-1 expression on donor endothelial cells did not reduce the overall number of graft-infiltrating cells significantly but instead resulted in a significant increase in infiltration by macrophages (F4/80 cells), leading to significantly elevated intragraft mRNA expression of inducible nitric oxide synthase. During the development of transplant arteriosclerosis, PECAM-1 donor endothelial cells were replaced by recipient PECAM-1 endothelial cells, a process that occurred only in the allogeneic situation. Endothelial replacement commenced 14 days after transplantation and was complete by day 30. CONCLUSIONS: These data suggest that PECAM-1 expression by donor endothelial cells attenuates the development of transplant arteriosclerosis, possibly by affecting macrophage infiltration.

Animals↗
PubMed2003

Expression of A20 in the vessel wall of rat-kidney allografts correlates with protection from transplant arteriosclerosis.

BACKGROUND: Chronic rejection with development of transplant arteriosclerosis is the major culprit involved in loss of kidney allografts. The allografts' fate was thought to depend on the intensity of the host immune responses and the potency of immunosuppressive regimens. Recent data suggests that grafts contribute to their own survival by way of up-regulation of "cytoprotective" genes. METHODS: We analyzed the expression of four cytoprotective genes, A20, Bcl-2, Bcl-x(L) and heme oxygenase (HO)-1, in three rat renal allograft models of chronic rejection: Fisher 344-Lewis (F344/Lew), Dark Agouti-Brown Norway (DA/BN), and DA-Wistar-Furth (WF). We chose these genes for their known anti-inflammatory and anti-apoptotic function in endothelial cells (EC) and the atheroprotective function of A20 in smooth muscle cells (SMC). RESULTS: Twenty-eight and 9 weeks following transplantation, F344/Lew and DA/BN transplants had stable graft function. Histopathologic analysis showed moderate tissue damage, minimal cellular infiltrates, and preserved vascular integrity correlating with high expression of A20 in SMC. Conversely, impaired allograft function in the DA/WF combination with substantial transplant arteriosclerosis was noted in 60% of the grafts correlating with absent or decreased A20 expression in EC and SMC. In all combinations, expression of HO-1, Bcl-2, and Bcl-x(L) colocalized with infiltrating cells and was not informative on the graft status. CONCLUSIONS: We demonstrate for the first time a strict correlation between A20 expression in the vessel and the absence of transplant arteriosclerosis in rat kidney-allograft models. This data is similar to data obtained in human kidney allografts and suggests that A20 may represent a novel therapeutic target for the prevention of chronic allograft rejection.

Animals↗
PubMed2005

Aging and transplant arteriosclerosis in absence of alloreactivity and immunosuppressive drugs in a rat aortic model: recipient age's contribution.

BACKGROUND: Almost half of all transplanted vascularized organ grafts will be lost to transplant arteriosclerosis sometime posttransplantation. Organ shortage for primary transplants and retransplants has led to donor-pool expansion to include elderly donors, knowing that aging per se promotes arteriosclerosis. The current understanding that donor age negatively affects organ and/or patient survival outcome is undermined by variables such as the use of immunosuppressive drugs, their toxicity to the graft, degree of donor-recipient histocompatibility, and the resulting chronic rejection. The purpose of this study was to determine whether the donor's age or recipient's age matters the most in transplant arteriosclerosis in the absence of such variables. METHODS: A syngeneic combination was used where young (2-month-old) and old (22-month-old) donor aortas were injured to initiate neointimal thickening, then transplanted into age-mismatched recipients for 14, 60, and 90 days and then assessed for neointimal thickening. Base level injury response due ischemia and surgery was evaluated in age-matched and noninjured aortic grafts, respectively. RESULTS: Young aortas invariably developed thicker neointima when transplanted into old recipients than when transplanted into young ones. Correspondingly, old aortas transplanted in young recipients consistently developed less neointimal thickening than when transplanted into old recipients. CONCLUSIONS: Our findings strongly suggest that the severity of age-related neointima formation is primarily determined by the recipient's age rather than the donor's age. Therefore, in addition to focusing on donor-specific tolerance induction, strategies aiming at increasing the lifespan of vascularized organ grafts also have to take into consideration the recipient's aging milieu.

Aging↗
PubMed1994

Effect of ganciclovir prophylaxis on cytomegalovirus-enhanced allograft arteriosclerosis.

Clinical and experimental studies have established the accelerating role of cytomegalovirus (CMV) infection on cardiac allograft arteriosclerosis, i.e. chronic rejection. In this study, we investigated the effect of ganciclovir prophylaxis on the development of CMV-enhanced allograft arteriosclerosis. Rat aortic allografts were done from DA donors to WF recipients and either infected with 10(5) plaque-forming units of rat CMV (RCMV) 1 day after transplantation or left uninfected. RCMV-infected allografts received ganciclovir at an initial dose of 20 mg/kg and a maintenance dose of 10 mg/kg twice a day for 14 days. Grafts were removed at 7, 14 days, and 1 and 3 months after transplantation and processed for morphometry and autoradiography. The results of this study demonstrated that ganciclovir prophylaxis significantly delays and reduces RCMV-enhanced allograft arteriosclerosis in the rat.

Animals↗