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PubMed2005

Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition.

BACKGROUND: Recent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro. METHODS: In the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 micromol/L and 30 micromol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis. RESULTS: We demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 +/- 3.5 microm vs control group, 64.0 +/- 7.1 microm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells. CONCLUSIONS: These novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting. CLINICAL RELEVANCE: Late graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting.

Animals↗

PubMed1984

The development of human benign prostatic hyperplasia with age.

In this study we report the prevalence and growth rate of human benign prostatic hyperplasia with age by combining and analyzing data from 10 independent studies containing more than 1,000 prostates. The normal prostate reaches 20 plus or minus 6 gm. in men between 21 and 30 years old, and this weight remains essentially constant with increasing age unless benign prostatic hyperplasia develops. The prevalence of pathological benign prostatic hyperplasia is only 8 per cent at the fourth decade; however, 50 per cent of the male population has pathological benign prostatic hyperplasia when they are 51 to 60 years old. The average weight of a prostate that is recognized at autopsy to contain benign prostatic hyperplasia is 33 plus or minus 16 gm. Only 4 per cent of the prostates in men more than 70 years old reach sizes greater than 100 gm. An analysis of a logistic growth curve of benign prostatic hyperplasia lesions removed at prostatectomy indicates that the growth of benign prostatic hyperplasia is initiated probably before the patient is 30 years old. The early phase of benign prostatic hyperplasia growth (men between 31 and 50 years old) is characterized by a doubling time for the tumor weight of 4.5 years. In the mid phase of benign prostatic hyperplasia growth (men between 51 and 70 years old) the doubling time is 10 years, and increases to more than 100 years in patients beyond 70 years old.

Adolescent↗

PubMed2003

Florid basal cell hyperplasia of the prostate: a histological, ultrastructural, and immunohistochemical analysis.

Basal cell proliferation is a common finding in a benign hyperplastic prostate gland. Occasionally, basal cell hyperplasia is so florid that it can be mistaken for prostatic adenocarcinoma. We characterized histological, ultrastructural, and immunohistochemical features of florid basal cell hyperplasia from transurethral resections (n = 11) and prostatectomy specimens (n = 4). Fifteen cases of prostatic adenocarcinoma were used as comparison. Intraluminal calcification was present in 40% of florid basal cell hyperplasia cases (6 of 15) and a unique finding of intracytoplasmic hyaline globules was detected in 53.3% of florid basal cell hyperplasia cases (8 of 15). Ultrastructural analysis revealed luminal calcification and intracytoplasmic electron-dense globules in foci of basal cell hyperplasia. Crystalloids, a frequent finding in low-grade prostate cancer, were absent in all 15 cases of florid basal cell hyperplasia. By immunohistochemistry, the basal cell-specific 34betaE12 and p63 as well as glutathione-s-transferase pi were positive in all basal cell hyperplasia cases but negative in all prostatic adenocarcinomas. These distinguishing features of florid basal cell hyperplasia are helpful in differential diagnosis from prostatic adenocarcinoma. Cytokeratins 8 and 18 were both positive in basal cells, benign secretory cells, and carcinoma cells, failing to be of discrimatory value. Immunostaining for alpha-methylacyl-coenzyme racemase, a new prostate cancer marker, was negative in hyperplastic basal cells but detected a distinct minor benign cell population in basal cell hyperplasia of possible neuroendocrine origin.

Adenocarcinoma↗

PubMed1994

Urinary bladder hyperplasia in the rat: non-specific pathogenetic considerations using a beta-lactam antibiotic.

Eight of the known chemical substances associated with neoplasia in man are known to target the urinary bladder urothelium. Preneoplastic changes have been identified following exposure to each of these chemicals, and they have also been seen to occur in many species of lab animals. The most important such change is preneoplastic hyperplasia. Adaptive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves disruption of homeostasis. Its severity increases with dose and time. It is not seen in controls but it is still reversible during the recovery segment after exposure to a toxic substance. When reparative hyperplasia continues beyond a certain threshold of time and dose, it progresses to preneoplastic hyperplasia, which further progresses with continued stimulation to frank neoplasia. The synthetic beta-lactam penem antibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive urothelial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 22101, it can be deduced that the morphologic finding of adaptive urothelial hyperplasia is caused by reduction of intravesicular urine pH. This effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in preclinical toxicity studies.

Animals↗

PubMed2006

Basic and clinical aspects of parathyroid hyperplasia in chronic kidney disease.

Marked parathyroid hyperplasia develops in patients with chronic kidney disease, especially those with long dialysis vintage. Although progression of hyperplasia is associated with downregulation of vitamin D receptor and calcium-sensing receptor, initial abnormality that triggers and maintains parathyroid cell proliferation, as well the critical abnormality for the progression of diffuse hyperplasia to nodular hyperplasia, still remains to be elucidated. It is quite important for the optimal management of renal osteodystrophy to recognize the development of nodular hyperplasia, because the cells in nodular hyperplasia are usually resistant to medical therapy and further treatment of such patients often leads to vascular calcification. For this purpose, size and blood supply of enlarged parathyroid glands have been used as good clinical markers. Furthermore, we have recently shown that the serum fibroblast growth factor 23 level can be used for predicting refractory hyperparathyroidism. Once nodular hyperplasia develops in any of the enlarged parathyroid glands, such patients need to be treated by parathyroid intervention including percutaneous ethanol injection therapy. In addition, as direct vitamin D injection therapy has been shown to induce regression of hyperplasia, it may become possible to reverse or normalize established nodular hyperplasia if we can develop new agents with such effects in the near future.

Anti-Infective Agents, Local↗

PubMed1999

Pseudoepitheliomatous hyperplasia in cutaneous T-cell lymphoma. A clinical, histopathological and immunohistochemical study with particular interest in epithelial growth factor expression. The French Study Group on Cutaneous Lymphoma.

Pseudoepitheliomatous hyperplasia has occasionally been reported in cutaneous T-cell lymphoma (CTCL). This association raises the question of the relationship between epidermal hyperplasia and the lymphomatous infiltrate. Because epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) have been demonstrated to be involved in epidermal proliferation through binding to EGF receptor (EGFr), we tested the hypothesis that these cytokines could be secreted by lymphomatous cells, and induce the overlying pseudoepitheliomatous hyperplasia. The purposes of this study were: (i) to describe the clinical and immunohistological features of pseudoepitheliomatous hyperplasia; (ii) to determine its frequency in a large series of CTCLs; and (iii) to evaluate the expression of EGF, TGF-alpha and EGFr in CTCL with or without pseudoepitheliomatous hyperplasia. Eleven cases of CTCL with pseudoepitheliomatous hyperplasia were collected from a series of 353 cases of cutaneous lymphoma registered from 1990 to 1996. They consisted of eight of 28 (28.5%) CD30+ large T-cell lymphomas and three of 148 (2%) cases of mycosis fungoides. Epidermal expression of EGF, EGFr and TGF-alpha was stronger in CTCL than in control normal human skin. Lymphomatous T cells expressed EGF and TGF-alpha whereas no expression of these cytokines could be detected in cutaneous and nodal B-cell lymphomas, nor in a normal lymph node. In addition, epidermal expression of EGFr was stronger in CTCL with pseudoepitheliomatous hyperplasia than in control cases of CTCL without pseudoepitheliomatous hyperplasia, suggesting that these cytokines, in association with other factors, are probably involved in the epidermal hyperplasia observed in some cases of CTCL.

Epidermal Growth Factor↗

PubMed2001

Atypical endometrial hyperplasia shares genomic abnormalities with endometrioid carcinoma by comparative genomic hybridization.

Endometrial hyperplasia is a common disorder that is now observed with increasing frequency in women treated with hormonal replacement therapy or with tamoxifen. This study was undertaken to determine whether genomic features of various forms of endometrial hyperplasias would allow their classification as a benign, premalignant, or malignant abnormality. Comparative genomic hybridization (CGH) was performed on endometrial glands microdissected by laser capture microscope from 19 archival endometrial samples, comprising 5 normal endometria, 1 polyp, 2 simple hyperplasias, 5 hyperplasias with nuclear abnormalities (atypical hyperplasias), and 4 low-grade and 2 high-grade endometrioid carcinomas, 1 with squamous component (adenoacanthoma). Genomic DNA, extracted from the glands and the squamous component in 1 case, was amplified by degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR) and compared with sex-matched DNA by CGH. No genomic imbalances were observed in the normal samples, the polyp, or the simple hyperplasias. However, in atypical hyperplasia, regardless of the level of cytologic atypia, genomic abnormalities were observed that also occurred in endometrioid carcinomas. Chromosomes 1, 8, and 10 were most often affected. The results are compared with molecular genetic abnormalities recently reported in these lesions. This study strongly suggests that atypical endometrial hyperplasias are closely related to endometrioid carcinoma and should be considered precancerous lesions, contrary to simple hyperplasia, which is a benign disorder. The squamous component of one of the high-grade carcinomas showed genetic abnormalities similar to those of endometrioid carcinoma and therefore does not represent squamous metaplasia but is an integral part of the malignant process.

Adult↗

PubMed2001

Folate supplementation inhibits intimal hyperplasia induced by a high-homocysteine diet in a rat carotid endarterectomy model.

OBJECTIVE: Hyperhomocysteinemia has been implicated as a causative factor in intimal hyperplasia development. The addition of dietary folate in a hyperhomocysteinemia, carotid endarterectomy rat model is postulated to decrease plasma homocysteine levels and, in turn, reduce post-carotid endarterectomy intimal hyperplasia. METHODS: Each rat was fed one of six diets: (1) lab chow with no folate (n = 7), (2) lab chow with 10 mg/kg folate added (n = 3), (3) lab chow with 25 mg/kg folate added (n = 3), (4) a homocysteine diet with no folate (n = 7), (5) a homocysteine diet with 10 mg/kg folate added (n = 5), or (6) homocysteine diet with 25 mg/kg folate added (n = 5). Each rat then underwent an open carotid endarterectomy. In 2 weeks, intimal hyperplasia in the carotid artery was measured. Plasma homocysteine and folate levels were measured. RESULTS: Plasma folate levels rose with folate administration. Plasma homocysteine in the lab chow group was 5.4 +/- 0.5 micromol/L and did not change with the addition of folate. In the homocysteine diet group, plasma homocysteine rose 10-fold over the lab chow group (51.9 +/- 6.5 vs 5.4 +/- 0.5, micromol/L, P <.0001). In the group fed a homocysteine diet with 10 mg/kg folate added, a significant decrease in plasma homocysteine was observed (17.5 +/- 8.5 vs 51.9 +/- 6.5, micromol/L, P =.0003). In the group fed a homocysteine diet with 25 mg/kg folate added, plasma homocysteine levels were further reduced to levels seen in the lab chow group (12.6 +/- 2.6 vs 5.4 +/- 0.5, micromol/L, P = not significant). The relationship between plasma folate and homocysteine was inverse (R = 0.39, P =.0036). Luminal stenosis due to intimal hyperplasia was minimal in lab chow groups and unaffected by folate. The homocysteine diet group demonstrated post-carotid endarterectomy luminal stenosis due to intimal hyperplasia (60.9% +/- 9.2%). In the group fed a homocysteine diet with 10 mg/kg folate added, intimal hyperplasia was reduced, compared with the homocysteine diet group (32.6% +/- 7.4% vs 60.9% +/- 9.2%, P =.009). In the group fed a homocysteine diet with 25 mg/kg folate added, intimal hyperplasia was reduced to lab chow group levels (10.8% +/- 0.8% vs 4.8% +/- 1.0%, P = not significant) and was reduced, compared with the group fed a homocysteine diet with 10 mg/kg folate added. CONCLUSION: The use of folate in this hyperhomocysteinemia carotid endarterectomy model and the resultant attenuation of plasma homocysteine elevation and intimal hyperplasia development lend strong support to homocysteine being an independent etiologic factor in post-carotid endarterectomy intimal hyperplasia.

Animals↗

PubMed1997

Treatment of cyclosporin-induced gingival hyperplasia with azithromycin.

BACKGROUND: Gingival hyperplasia is a known complication of cyclosporin therapy. Although plaque control has been shown to be of benefit, gingival surgery is occasionally necessary. The aim of this study was to review the effect of a short-course therapy with azithromycin in renal transplant patients with cyclosporin-induced gingival hyperplasia. METHODS: Thirty-eight patients received 500 mg/day of azithromycin for 3 consecutive days. The degree of gingival hyperplasia was classified as: 0, no gingival overgrowth; 1, mild overgrowth; 2, moderate overgrowth, and 3, severe overgrowth. Gingival bleeding and evolution of gingival hyperplasia were determined at 0 (pretreatment), 7, 30, 90 and 180 days. Cyclosporin, serum creatinine and ALT levels were simultaneously determined on the same days. RESULTS: Seven patients were excluded, leaving a total of 31 included in the trial. Eleven had a score of 3, 17 a score of 2, and 3 a score of 1. The degree of gingival hyperplasia was unrelated to the dose and levels of cyclosporin. Gingival hyperplasia improved in all patients (P < 0.001, Friedman test). The degree of improvement was better when the degree of hyperplasia was lower. In 27 patients gingival hyperplasia remained absent 6 months later, 3 patients required a second course of treatment, and another required gingival surgery. Gingival bleeding, present in 28 patients when diagnosed, disappeared in all cases in 2.2 +/- 1.2 (1-7) days. No adverse effects were observed. Cyclosporin, serum creatinine, and ALT levels were not affected by treatment. CONCLUSIONS: Azithromycin improves cyclosporin-associated gingival hyperplasia, especially when administered early in the process.

Adult↗

PubMed2000

The hyperplasia-to-carcinoma sequence in the breast. Immunohistochemical-histologic correlations.

Breast cancer is probably the result of a series of genetic events, each with its own histopathologic correlate in the hyperplasia to carcinoma sequence. The expression of breast cancer markers in hyperplasia and tumors are well known, but few studies have investigated their sequential expression among hyperplastic and cancerous lesions within the same breast. Using breast tissue obtained from a single procedure, we correlated the immunohistochemical expression of several breast cancer markers with the histopathologic stage of proliferative breast disease. We selected 14 cases in which various degrees of hyperplasia coexisted with carcinoma. Serial sections were reacted with antibodies to DF3, c-erbB-2, p53 (DO7 and CM1), B72.3, and cyclin D1. We found that within an individual breast, the number of breast cancer markers expressed increased with progression from hyperplasia to atypical hyperplasia to carcinoma. Cytoplasmic DF3 was first expressed at the level of simple hyperplasia, followed by c-erbB-2 in atypical hyperplasia. Overexpression of p53 was confined to carcinomas, and thus appeared to be a late event. B72.3 was expressed in three carcinomas and in one atypical hyperplasia, although the associated carcinoma was negative. Carcinomas that expressed cytoplasmic DF3 and c-erbB-2 were associated with atypical hyperplasias that also expressed cytoplasmic DF3 and c-erbB-2, with one and two exceptions, respectively. No specific cyclin D1 staining pattern was observed.

Antibodies↗

PubMed2006

GLUT-1 is preferentially expressed in atypical endometrial hyperplasia and endometrial adenocarcinoma.

The facilitative transport of monosaccharides in human cells is accomplished by a family of transmembrane proteins, GLUT-1 to GLUT-7, that differ in their tissue distribution, affinities for specific monosaccharides, and physiologic regulation. GLUT-1, a high-affinity glucose transporter, is normally expressed in erythrocytes, the perineurium of peripheral nerves, and capillary endothelial cells of the blood-brain barrier. Although the aberrant expression of GLUT-1 has been reported in a wide spectrum of epithelial malignancies, its possible correlation with the malignant transformation of endometrial epithelium has not been clearly established. The purpose of this study was to evaluate the extent to which benign, hyperplastic, atypical, and malignant endometrial epithelia express GLUT-1. The authors examined the IHC expression of GLUT-1 in cases of proliferative endometrium (n=12), secretory endometrium (n=10), endometrial polyps (n=10), adenomyosis (n=18), simple hyperplasia (n=14), complex hyperplasia without atypia (n=17), complex hyperplasia with atypia (n=17), and adenocarcinoma (n=31). Positive staining was defined as distinct, linear membrane staining, particularly at cell-cell borders. Cells that showed only cytoplasmic staining were considered negative. The percentages of positive cells and staining intensity were assessed in a semiquantitative fashion and scored (1+ to 3+). All cases from proliferative endometrium, secretory endometrium, adenomyosis, and simple hyperplasia and 90% (9/10 cases) of the endometrial polyps were negative for GLUT-1. GLUT-1 was expressed in 24% (4/17 cases) of complex hyperplasia without atypia, 71% (12/17 cases) of complex hyperplasia with atypia, and 90% (28/31 cases) of adenocarcinomas. The extent of staining ranged from occasional positive foci to extensive multifocal staining. GLUT-1 positivity increased in intensity as the distance of tumor cells to stroma increased. The authors conclude that GLUT-1 is preferentially expressed in complex hyperplasia with atypia and in adenocarcinoma and that GLUT-1 immunostaining is useful in distinguishing benign hyperplasia from hyperplasia strongly associated with malignancy. GLUT-1-mediated glucose transport may allow hypoxic tumor cells distant from stromal blood vessels to survive through glycolysis. These data suggest that the expression of GLUT-1 transporter may be closely related to the malignant transformation of epithelial endometrial tumors by supporting their increased need for glucose metabolism.

Adenocarcinoma↗

PubMed2004

Treatment of endometrial hyperplasia with a danazol-releasing intrauterine device: a prospective study.

The purpose of the present study was to assess the effect of a danazol-releasing intrauterine device (D-IUD) in the treatment of endometrial hyperplasia. Twenty patients with endometrial hyperplasia including 14 with simple endometrial hyperplasia and 2 with complex endometrial hyperplasia (group A), and 4 with atypical endometrial hyperplasia (group B) were enrolled in the prospective study between August 1999 and December 2003. During and just after the treatment, improvement was seen in all patients. Simple or complex endometrial hyperplasia (group A) demonstrated regression to a normal secretory endometrium (38% of group A), pseudodecidual stromal change (31%) and glandular atrophy (25%), and miscellaneous change (inflammation, necrosis, etc.) (38%). Atypical hyperplasia (group B) demonstrated regression to a normal secretory endometrium (25% of group B), pseudodecidual stromal change (75%), glandular atrophy (50%) and miscellaneous change (granulation) (25%). In group A, 2 women conceived after completion of the treatment. The recurrence rate in patients with endometrial hyperplasia (groups A and B) in the follow- up was 20% and acceptable as compared with other studies. The pretreatment menstrual interval patterns of the patients were maintained peri- and post-treatment. These data indicate that D-IUD therapy might be a novel and effective method for the treatment of endometrial hyperplasia.

Adult↗

PubMed2005

Treatment of non-atypic endometrial hyperplasia using thermal balloon endometrial ablation therapy.

BACKGROUND/AIM: Traditionally endometrial hyperplasias have been treated with progestins. Unfortunately, quite often hyperplasias are resistant to treatment, or they recur after therapy. The aim of the study was to compare traditional progestin administration with thermal balloon endometrial ablation in the treatment of non-atypic endometrial hyperplasia. METHODS: Women with endometrial hyperplasia (n = 34) were randomized in a 1:1 allocation ratio. Endometrial biopsy samples were taken 6 and 12 months after the treatment; if any signs of hyperplasia were detected, hysterectomy was performed. In addition, the hospital records were checked in September 2003 to observe for any later hysterectomy. Main outcome measures were recovery from hyperplasia and avoidance of hysterectomy. RESULTS: In patients treated with thermal ablation, the hyperplasias persisted at 6 or 12 months in 4 out of 17 patients, whereas the rate was 6 out of 17 patients in the progestin therapy group. According to patient records, 1 further patient treated with thermal ablation and 3 further patients treated with progestin were hysterectomized after the last visit. A total of 14 of the 34 patients (41%) have been hysterectomized so far. CONCLUSIONS: These preliminary results suggest that thermal balloon endometrial ablation therapy seems to be as effective as traditional progestin administration in the treatment of non-atypic endometrial hyperplasia. The hysterectomy rate during the follow-up period was, however, considerably high, and, therefore, hysterectomy might be considered even a first-choice treatment for endometrial hyperplasias.

Adult↗

PubMedDate not supplied

Criteria for differential diagnosis of complex hyperplasia or beyond in endometrial cytology.

OBJECTIVE: To establish qualitative criteria for diagnosing complex hyperplasia, complex atypical hyperplasia and well-differentiated adenocarcinoma in endometrial cytology. STUDY DESIGN: The frequency of appearance of papillary and arborescent cell clusters and the morphology of type A stromal bundles in arborescent cell clusters were examined in 59 samples of complex hyperplasia, 23 of complex atypical hyperplasia, 77 of well-differentiated adenocarcinoma and 40 of normal endometrium. RESULTS: Papillary cell clusters were observed in all samples of hyperplasia and adenocarcinoma. The rate of observation of arborescent cell clusters increased proportionately to the progress from complex hyperplasia to complex atypical hyperplasia to well-differentiated adenocarcinoma. No arborescent cell clusters were found in normal endometrium. Primary branching and the number of layers of type A stromal bundles also increased with the progress toward complex hyperplasia and well-differentiated adenocarcinoma. Secondary and further branching was observed in large numbers in cases of adenocarcinoma. CONCLUSION: For detection of complex hyperplasia or lesions beyond it in endometrial cytology, it is important to observe the presence of papillary clusters. For differentiation of the various lesions, it is important to observe the presence of arborescent clusters as well as type A stromata inside the clusters.

Adenocarcinoma↗

PubMed2004

Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia.

OBJECTIVE: Phosphoinositide (PI) 3-kinase promotes vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia. We recently demonstrated that the inositol 3-phosphatase PTEN is expressed in VSMCs and that its overexpression inhibits these cellular responses. The purpose of this study was to determine the effects of adenovirus-mediated overexpression of PTEN on neointimal hyperplasia in vivo in the rat carotid injury model. METHODS AND RESULTS: Rat carotid arteries were balloon-injured and treated with a recombinant control adenovirus (AdEV) (n=6), an adenovirus encoding wild-type PTEN (AdPTEN) (n=8), or phosphate-buffered saline (sham) (n=5). Injured vessels demonstrated PTEN overexpression by Western blotting and immunohistochemistry after AdPTEN treatment. Neointimal hyperplasia was assessed 2 weeks after balloon injury and adenovirus administration. Compared with controls, AdPTEN treatment significantly decreased neointimal area and percent stenosis. To investigate the mechanisms of action of AdPTEN, vessels were harvested 3 days after balloon injury and virus infection. AdPTEN significantly increased medial cell apoptosis while decreasing proliferation of the remaining viable cells. CONCLUSIONS: PTEN overexpression potently inhibits neointimal hyperplasia through induction of apoptosis and inhibition of medial cell proliferation. These findings suggest that modulation of PTEN expression or activity may be a viable approach to treat neointimal hyperplasia. Phosphoinositide (PI) 3-kinase is a critical regulator of neointimal hyperplasia. The inositol 3-phosphatase PTEN modulates PI 3-kinase signaling by hydrolyzing the phospholipid products of PI 3-kinase, and overexpression of PTEN in vascular smooth muscle cells inhibits the cellular processes necessary for neointimal hyperplasia. The effects of adenovirus-mediated PTEN (AdPTEN) overexpression on neointimal hyperplasia were tested in the rat carotid injury model. Compared with control arteries, AdPTEN treatment significantly reduced neointimal area and percent stenosis by enhancing medial cell apoptosis and inhibiting proliferation of the remaining viable cells. Thus, PTEN provides a new target for the treatment of neointimal hyperplasia.

Adenoviridae↗

PubMedDate not supplied

Saratin, an inhibitor of collagen-platelet interaction, decreases venous anastomotic intimal hyperplasia in a canine dialysis access model.

Prosthetic dialysis access thrombosis and/or stenosis is the most common cause of graft impairment or loss and is primarily attributed to venous outflow stenosis due to intimal hyperplasia. Intimal hyperplasia is thought to result from interactions between areas of exposed subendothelial collagen in an injured vessel and platelets, resulting in platelet adhesion. Saratin, an inhibitor of the vWF-dependent binding of platelet to collagen interaction, has been shown in vitro to reduce the adhesion of platelets to collagen. In the current study, the authors investigated the effects of topical saratin administration in a canine dialysis access model in regard to intimal hyperplasia development at the venous anastomosis. Fourteen female mongrel dogs underwent placement of a femoral polytetrafluoroethylene (PTFE) dialysis access graft and were placed into 1 of 2 groups: 1) control or 2) experimental with topical saratin application. The experimental group had 600 microg of saratin (1 microg/microL) applied for 5 minutes directly onto the venous anastomosis before restoration of blood flow;control groups received vehicle control. At 4 weeks postoperative, a portion of the graft was removed along with a segment of the outflow vein. Veins were subsequently processed, sectioned, and analyzed along the length of the excised segment and divided into blocks that included the area of the graft toe, midanastomotic region and heel, and blocks A-E. Intimal hyperplasia was assessed by a computer-assisted morphometric analysis. Platelet counts and bleeding times were also measured. Vein segments in the control group (n=7) showed pronounced intimal hyperplasia in blocks B, C, and D as compared to the saratin group (n=6). Distribution of intimal hyperplasia by blocks between control and saratin groups were as follows: block [A] 8.6 +/- 1.9 vs 9.7 +/- 3.0% (p=NS), [B] 32.7 +/- 6.3 vs 10.7 +/- 3.5% (p=0.01), [C] 44.8 +/- 6.2% vs 10.3 +/- 1.5% (p=0.0004), [D] 40.8 +/- 11.0 vs 9.1 +/- 4.2% (p=0.02), [E] 7.5 +/- 5.5 vs 2.7 +/- 0.4% (p=NS). Intimal hyperplasia normalized to vein wall thickness also showed a significant reduction with saratin application. Bleeding times and platelet counts obtained at different time points during the experiment showed no difference between control and saratin groups. In a canine dialysis access model using PTFE grafts, topical application of saratin at the venous anastomosis decreased intimal hyperplasia development by as much as 77% when compared with control animals. Saratin provides for a method of substantially reducing intimal hyperplasia by direct local application without systemic side effects.

Anastomosis, Surgical↗

PubMed2003

Neovascularization in intimal hyperplasia is associated with vein graft failure after coronary artery bypass surgery.

Vein graft atherosclerosis is the major limitation of arterial bypass surgery. This study was carried out to determine if the number of microvessels per area of intimal hyperplasia correlated with vein graft disease. Vein grafts (n=24, graft age range 2-19 years) were taken from 22 patients undergoing redo-coronary artery bypass surgery. Mean age of the patients was 68 +/- 9 years; 92% were males. Samples were divided into three groups (n=8 per group): in group I segments were from grafts without angiographic or histologic disease, in groups II and III segments were from grafts with significant angiographic stenosis, without (group II) and with (group III) atheroma. Intimal hyperplasia was identified by Masson staining, morphometric analysis was performed with NIH image analysis software. Microvessels in the intimal hyperplasia were identified using immunohistochemical techniques. Significance was determined by single-factor ANOVA p < 0.05. The mean area of intimal hyperplasia was similar in groups I and II at 1.06 +/- 0.25 mm2 and 0.97 +/- 0.37 mm2, respectively. The extent of intimal hyperplasia was significantly greater in group III, 1.70 +/- 0.62 mm2 (p < 0.01). In group I, the microvessel count in the intimal hyperplasia was 5.62 +/- 3.89 vessels/mm2, while in group III it was 15.26 +/- 3.66/mm2 (p < 0.01 versus group I). Interestingly the number of microvessels per area of intimal hyperplasia in group II was similar to that in group III). In this study, the extent of neovascularization in intimal hyperplasia correlated with stenoses in human vein grafts. Strategies designed to limit neovascularization in intimal hyperplasia may lead to novel therapies to prevent vein graft failure.

Aged↗

PubMedDate not supplied

Effect of clopidogrel on platelet aggregation and intimal hyperplasia following carotid endarterectomy in the rat.

Intimal hyperplasia results in significant morbidity and mortality following vascular intervention. Both platelets and elevated homocysteine have been implicated in the development of intimal hyperplasia. We previously demonstrated that a locally applied antiplatelet agent decreases the development of intimal hyperplasia. We were therefore interested in a systemic antiplatelet agent, clopidogrel. We hypothesized that clopidogrel would decrease platelet aggregation and activity and intimal hyperplasia. Male Sprague-Dawley rats underwent carotid endarterectomy (CEA) and treatment with either placebo or varying regimens of clopidogrel, including chronic, pre-CEA bolus, chronic plus pre-CEA bolus, and chronic plus post-CEA bolus; a homocystine diet was used to elevate both plasma homocysteine and the degree of intimal hyperplasia. Platelet aggregation, platelet activity, and intimal hyperplasia were then assessed. Platelet aggregation was not decreased with chronic clopidogrel; however, it was decreased with pre-CEA bolus clopidogrel. Similarly, platelet activity was not inhibited by chronic clopidogrel but was inhibited by pre-CEA and chronic plus pre-CEA bolus clopidogrel. Neither chronic, pre-CEA bolus, chronic plus pre-CEA bolus, nor chronic plus post-CEA bolus clopidogrel resulted in a decrease in intimal hyperplasia. Although pre-CEA bolus clopidogrel resulted in a decrease in both platelet aggregation and activity, it was unable to decrease the development of intimal hyperplasia at any dose. Additional factors must therefore contribute to the pathologic development of intimal hyperplasia.

Animals↗