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Biomedical subjects

Lloyd Paul Aiello

Publications and source records attributed to Lloyd Paul Aiello.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema.

OBJECTIVE: To compare optical coherence tomography (OCT)-measured retinal thickness and visual acuity in eyes with diabetic macular edema (DME) both before and after macular laser photocoagulation. DESIGN: Cross-sectional and longitudinal study. PARTICIPANTS: Two hundred ten patients (251 eyes) with DME enrolled in a randomized clinical trial of laser techniques. METHODS: Retinal thickness was measured with OCT and visual acuity was measured with the electronic Early Treatment of Diabetic Retinopathy procedure. MAIN OUTCOME MEASURES: Optical coherence tomography-measured center point thickness and visual acuity. RESULTS: The correlation coefficients for visual acuity versus OCT center point thickness were 0.52 at baseline and 0.49, 0.36, and 0.38 at 3.5, 8, and 12 months after laser photocoagulation. The slope of the best fit line to the baseline data was approximately 4.4 letters (95% confidence interval, 3.5-5.3) of better of visual acuity for every 100-mum decrease in center point thickness at baseline with no important difference at follow-up visits. Approximately one third of the variation in visual acuity could be predicted by a linear regression model that incorporated OCT center point thickness, age, hemoglobin A1C, and severity of fluorescein leakage. The correlation between change in visual acuity and change in OCT center point thickening 3.5 months after laser treatment was 0.44, with no important difference at the other follow-up times. A subset of eyes showed paradoxical improvements in visual acuity with increased center point thickening (7%-17% at the 3 time points) or paradoxical worsening of visual acuity with a decrease in center point thickening (18%-26% at the 3 time points). CONCLUSIONS: There is modest correlation between OCT-measured center point thickness and visual acuity, and modest correlation of changes in retinal thickening and visual acuity after focal laser treatment for DME. However, a wide range of visual acuity may be observed for a given degree of retinal edema. Thus, although OCT measurements of retinal thickness represent an important tool in clinical evaluation, they cannot substitute reliably as a surrogate for visual acuity at a given point in time. This study does not address whether short-term changes on OCT are predictive of long-term effects on visual acuity.

Diabetic Retinopathy↗
PubMed2006

Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy.

OBJECTIVE: To evaluate the effect of ruboxistaurin, an orally administered protein kinase C beta (PKC beta) isozyme-selective inhibitor, on vision loss in patients with diabetes. DESIGN: Thirty-six-month, randomized, double-masked, placebo-controlled, parallel, multicenter trial. PARTICIPANTS: Six hundred eighty-five patients randomized at 70 clinical sites. METHODS: Ophthalmologic examination was performed at screening and at each 3-month visit. Retinopathy status was assessed every 6 months with Early Treatment Diabetic Retinopathy Study (ETDRS) standard 7-field 30 degrees color stereoscopic fundus photography. Levels of diabetic retinopathy and diabetic macular edema were determined by 2 independent graders masked to site and treatment assignment, with additional independent adjudication as required. Eligible patients had a best-corrected visual acuity (VA) score of > or =45 letters, retinopathy level > or = 47A and < or = 53E, and no prior panretinal photocoagulation in at least one eye. MAIN OUTCOME MEASURE: Effect of oral ruboxistaurin (32 mg/day) on reduction of sustained moderate visual loss (> or =15-letter decrease in ETDRS VA score maintained > or = 6 months) in patients with moderately severe to very severe nonproliferative diabetic retinopathy. RESULTS: Sustained moderate visual loss occurred in 9.1% of placebo-treated patients versus 5.5% of ruboxistaurin-treated patients (40% risk reduction, P = 0.034). Mean VA was better in the ruboxistaurin-treated patients after 12 months. Baseline-to-end point visual improvement of > or =15 letters was more frequent (4.9% vs. 2.4%) and > or =15-letter worsening was less frequent (6.7% vs. 9.9%) in ruboxistaurin-treated patients relative to placebo (P = 0.005). When clinically significant macular edema was >100 microm from the center of the macula at baseline, ruboxistaurin treatment was associated with less frequent progression of edema to within 100 microm (68% vs. 50%, P = 0.003). Initial laser treatment for macular edema was 26% less frequent in eyes of ruboxistaurin-treated patients (P = 0.008). CONCLUSION: Oral ruboxistaurin treatment reduced vision loss, need for laser treatment, and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy.

Administration, Oral↗
PubMed2006

Diurnal variation in retinal thickening measurement by optical coherence tomography in center-involved diabetic macular edema.

OBJECTIVE: To evaluate diurnal variation in retinal thickness measured with optical coherence tomography (OCT) in patients with center-involved diabetic macular edema. METHODS: Serial OCT3 measurements were performed in 156 eyes of 96 subjects with clinically diagnosed diabetic macular edema and OCT central subfield retinal thickness of 225 microm or greater at 8 am. Central subfield thickness was measured from OCT3 retinal thickness maps at 6 points over a single day between 8 am and 4 pm. A change in central subfield thickening (observed thickness minus mean normal thickness) of at least 25% and of at least 50 microm at 2 consecutive points or between 8 am and 4 pm was considered to have met the composite outcome threshold. RESULTS: At 8 am, the mean central subfield thickness was 368 microm and the mean visual acuity was 66 letters (approximately 20/50). The mean change in relative central subfield retinal thickening between 8 am and 4 pm was a decrease of 6% (95% confidence interval, -9% to -3%) and the mean absolute change was a decrease of 13 microm (95% CI, -17 to -8). The absolute change was significantly greater in retinas that were thicker at 8 am (P<.001) but the relative change was not (P = .14). The composite threshold of reduction in central subfield thickening (as defined above) was observed in 5 eyes of 4 subjects (3% of eyes; 95% CI, 1% to 8%) while 2 eyes of 2 subjects (1%; 95% CI, 0% to 5%) had an increase in central subfield thickening of this same magnitude. The maximum decrease was observed at 4 pm in all 5 eyes. CONCLUSION: Although on average there are slight decreases in retinal thickening during the day, most eyes with diabetic macular edema have little meaningful change in OCT central subfield thickening between 8 am and 4 pm.

Anthropometry↗
PubMed2006

Comparison of nonmydriatic digital retinal imaging versus dilated ophthalmic examination for nondiabetic eye disease in persons with diabetes.

OBJECTIVE: To evaluate the ability of stereoscopic nonmydriatic digital retinal imaging to detect ocular pathologic features other than diabetic retinopathy (DR) in patients with diabetes mellitus (DM) compared with dilated retinal examination by retinal specialist ophthalmologists. DESIGN: Clinic-based comparative instrument study and retrospective chart review. PARTICIPANTS: Two hundred eighty Joslin Diabetes Center outpatients (560 eyes) with type 1 or type 2 DM. METHODS: Nonsimultaneous stereoscopic nonmydriatic digital retinal images (640 x 480 pixels) of three 45 degrees retinal fields were acquired and graded for clinical level of DR and other ocular pathologic features by certified readers according to Joslin Vision Network (JVN) protocol. Retrospective chart review compared findings from JVN digital images with findings from dilated retinal examination by retinal specialists performed within an average of 39.6 days of digital imaging. An independent senior retinal specialist adjudicated disagreements by review of 7 standard field 35-mm Early Treatment Diabetic Retinopathy Study protocol fundus photographs and JVN images. MAIN OUTCOME MEASURES: Detection of non-DR ocular pathologic features by digital imaging as compared with clinical examination. RESULTS: Nonmydriatic digital evaluation identified at least 1 non-DR ocular finding in 40.7% of patients (114/280). Non-diabetes mellitus ocular pathologic features identified by digital images, clinical examination, or both included cataract (n = 100); age-related maculopathy (n = 52); suspicion of glaucoma (n = 18); choroidal lesions (n = 18); evidence of systemic disorder (e.g., hypertension or renal disease; n = 15); epiretinal membrane (n = 11); chorioretinal atrophy, scar, or both (n = 6); retinal emboli (n = 3); retinitis pigmentosa (n = 1); and asteroid hyalosis (n = 1). Agreement of nonmydriatic imaging with clinical examination for presence and absence of these findings was 95.4%, 91.3%, 98.2%, 98.6%, 98.2%, 99.6%, 100%, 100%, 100%, and 100%, respectively. Kappa values for all non-DR lesions demonstrated near perfect agreement (kappa> or =0.80) except for age-related maculopathy (kappa = 0.71) and choroidal lesions (kappa = 0.73), where agreement was substantial. Overall, only 55 eyes (9.8%) were ungradable for level of DR and 85 eyes (15.2%) were ungradable for macular edema. CONCLUSIONS: Joslin Vision Network nonmydriatic digital imaging demonstrated excellent agreement with dilated ophthalmic examination by retinal specialists in the detection of ocular disease other than DR, suggesting a potential role for this technology in evaluating non-DR disorders and highlighting the extent of findings other than retinopathy in patients with diabetes.

Adult↗
PubMed2006

Bactericidal/permeability-increasing protein's signaling pathways and its retinal trophic and anti-angiogenic effects.

Bactericidal/permeability-increasing protein (BPI) was originally identified as a lipopolysaccharide (LPS) binding protein with gram-negative bactericidal activity in the leukocytes. In this study, we characterized the previously unknown effects of BPI in the eye and the molecular mechanisms involved in its action. BPI mRNA was detected in bovine retina; retinal pigment epithelium; and primary cultures of bovine retinal pigment epithelial cells (RPE), pericytes (RPC), and endothelial cells (REC); while BPI protein was measured in human vitreous and plasma. BPI, but not control protein thaumatin, activated extracellular regulated kinase (ERK) and AKT, and increased DNA synthesis in RPE and RPC but not in REC. A human recombinant 21 kDa modified amino-terminal fragment of BPI (rBPI21) reduced H2O2-induced apoptosis in RPE and inhibited vascular endothelial growth factor (VEGF)-stimulated ERK phosphorylation in REC when preincubated with VEGF. Intraperitoneal (i.p.)-injected rBPI21 reduced ischemia-induced retinal neovascularization and diabetes-induced retinal permeability. Since BPI has unusual dual properties of promoting RPC and RPE growth while suppressing VEGF-induced REC growth and vascular permeability, the mechanistic understanding of BPI's action may provide novel therapeutic opportunities for diabetic retinopathy and age-related macular degeneration.

Angiogenesis Inhibitors↗
PubMed2006

Hepatocyte growth factor induces retinal vascular permeability via MAP-kinase and PI-3 kinase without altering retinal hemodynamics.

PURPOSE: Although vascular endothelial growth factor (VEGF) is a key mediator of retinal vascular permeability (RVP), there may be additional humoral contributors. Hepatocyte growth factor (HGF) induces endothelial cell separation, regulates expression of cell adhesion molecules and is increased in the vitreous fluid of patients with proliferative diabetic retinopathy. The purpose of this study was to evaluate the in vivo effects of HGF on RVP and retinal hemodynamics and delineate the signaling pathways. METHODS: RVP was assessed by vitreous fluorescein fluorophotometry in rats. Time course and dose-response were determined after intravitreal HGF injection. MAP kinase (MAPK), phosphatidylinositol 3-kinase (PI-3 kinase), and protein kinase C (PKC) involvement were examined by using selective inhibitors. Retinal blood flow (RBF) and mean circulation time (MCT) were evaluated by video fluorescein angiography. RESULTS: HGF increased RVP in a time- and dose-dependent manner. HGF-induced RVP was evident 5 minutes after injection, and reached maximal levels after 25 minutes (+107% versus vehicle, P=0.002). This effect was comparable to that of maximum VEGF stimulation (134%+/-128% at 25 ng/mL). Selective inhibitors of MAPK (PD98059) and PI-3 kinase (LY294002) suppressed HGF-induced RVP by 86%+/-44% (P=0.015) and 97%+/-59% (P=0.021), respectively. Non-isoform-selective inhibition of PKC did not significantly decrease HGF-induced RVP. Although VEGF increases RBF and reduces MCT, HGF did not affect either. CONCLUSIONS: HGF increases RVP in a time- and dose-dependent manner at physiologically relevant concentrations with a magnitude and profile similar to that of VEGF, without affecting retinal hemodynamics. Thus, HGF may represent another clinically significant contributor to retinal edema distinct from the actions of VEGF.

Animals↗
PubMed2006

Inhibition of PKC beta by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients.

PURPOSE: To assess ocular and systemic safety and pharmacodynamic effects of the oral PKC beta selective inhibitor ruboxistaurin (RBX; LY333531) mesylate in patients with diabetes. METHODS: This was a double-masked, placebo-controlled, parallel, randomized, single-center clinical study evaluating the effect of oral administration of RBX (8 mg twice a day, 16 mg per day, or 16 mg twice a day) or placebo for 28 days in patients with no or very mild diabetic retinopathy on mean retinal circulation time (RCT), retinal blood flow (RBF), treatment-emergent adverse events, and other safety parameters. RESULTS: Twenty-nine persons aged 18 to 65 years with type 1 or 2 diabetes were evaluated. The only treatment-emergent adverse event with a statistically significant difference among treatment groups was abdominal pain, which was more common in placebo-treated subjects (P = 0.049). Statistically significant effects of RBX were observed on several hematologic and laboratory parameters, but values were within the normal reference range and none of the changes was deemed clinically meaningful. In patients receiving 16 mg RBX twice daily, the diabetes-induced increase in RCT was ameliorated, with a baseline-to-endpoint difference of -0.84 seconds (P = 0.046) relative to placebo. Increasing RBX dose was linearly associated with greater effect on RCT (P = 0.03). Similar results were observed with RBF. CONCLUSIONS: RBX was well tolerated at doses up to 16 mg twice daily for 28 days in patients with diabetes. It ameliorated diabetes-induced RCT abnormalities. No serious safety problems were identified in this patient population. Compared with prior published data, these findings represent the first direct human evidence of both bioavailability of RBX to retinal vessels and amelioration of diabetes-induced retinal hemodynamic abnormalities by an oral PKC beta inhibitor.

Administration, Oral↗
PubMed2005

Nonmydriatic digital imaging alternative for annual retinal examination in persons with previously documented no or mild diabetic retinopathy.

PURPOSE: To prospectively evaluate the Joslin Vision Network (JVN) for follow-up annual retinal examination for level of diabetic retinopathy (DR). DESIGN: Prospective cohort study. METHODS: Fifty-two patients with no or mild nonproliferative DR (Early Treatment Diabetic Retinopathy Study [ETDRS] level < or = 35) and no diabetic macular edema (DME) at dilated retinal examination 11 or more months earlier were imaged. Patients then had dilated retinal examination and color 35-mm seven standard field stereoscopic photography (ETDRS photographs) and completed a satisfaction survey. Level of DR determined from JVN images, clinical examination, and ETDRS photographs was compared. RESULTS: Two (1.9%) eyes had JVN images ungradable for level of DR. In the 102 gradable eyes (98.1%), JVN diagnosis exactly matched clinical examination for level of DR in 82 eyes (77.9%) and was within one level of DR in all eyes (100%). Three eyes (2.9%) had JVN images ungradable for DME; one of these eyes had DME by clinical examination. JVN diagnosis matched clinical examination for DME in all eyes (101) gradable by JVN. Fifty patients (96.1%) reported JVN imaging improved their understanding of eye disease, 100% were satisfied with JVN, and forty-eight (92.3%) would consider replacing dilated examination by their eye doctor with JVN imaging. CONCLUSIONS: JVN digital imaging closely matched clinical examination for level of DR and DME, would have resulted in no patients receiving less stringent follow-up, and was well accepted by patients. JVN digital imaging may be a suitable alternative for annual dilated retinal examination for determining level of DR or DME and appropriate follow-up comprehensive ophthalmic examination.

Adolescent↗
PubMed2005

A telemedicine program for diabetic retinopathy in a Veterans Affairs Medical Center--the Joslin Vision Network Eye Health Care Model.

PURPOSE: To extend access to diabetic eye care and characterize the extent of diabetic retinopathy {DR) and other ocular findings using the Joslin Vision Network (JVN). DESIGN: Retrospective observational cohort study. METHODS: Outpatients at the Togus VA Medical Center with diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance underwent JVN protocol imaging. Images were transmitted to the Joslin Diabetes Center for grading and recommended treatment plan. RESULTS: The study included 1,219 patients (2,437 eyes); 1,536 eyes (63.0%) had no (DR), 389 (16.0%) had mild nonproliferative DR (NPDR), 105 (4.3%) moderate NPDR, 35 (1.4%) severe NPDR, 20 (0.8%) very severe NPDR, and 21 (0.9%) had proliferative DR (PDR). Regarding diabetic macular edema (DME), 1,907 eyes (78.3%) had no DME, 34 (1.4%) had early DME, and 16 (0.7%) had clinically significant macular edema (CSME). Of all patients, 354 (29.0%) had either no DR or mild NPDR in both eyes, no evidence of DME, and no significant nondiabetic findings; 679 (55.7%) had no DR in either eye, and 229 (18.8%) had mild NPDR in the more severe eye. Of the 908 patients (74.5%) with either no DR or mild NPDR in the more severe eye, 533 (58.7%) had at least one nondiabetic ocular finding necessitating referral. Finally, 320 eyes (13.1%) were ungradable for both DR and DME and 160 (6.6%) were ungradable for DME alone. CONCLUSION: In a non-ophthalmic setting, JVN identifies the severity of DR and nondiabetic ocular conditions, permitting appropriate triage for eye care.

Adult↗
PubMed2005

Effect of ruboxistaurin on blood-retinal barrier permeability in relation to severity of leakage in diabetic macular edema.

PURPOSE: The purpose of the study was to investigate the effect of orally administered ruboxistaurin (RBX, LY333531), a selective protein kinase C beta inhibitor, on the permeability of the blood-retinal barrier in patients with diabetic macular edema. METHODS: Forty-one patients with diabetic macular edema were randomly assigned to an 18-month randomized, placebo-controlled, double-masked trial including four study arms (4, 16, or 32 mg/d RBX, or placebo). The RBX group comprised 30 patients (42 eyes) and the placebo group 11 patients (13 eyes). Retinal vascular leakage was assessed using vitreous fluorometry at baseline and after 3, 12, and 18 months. Statistical analysis of the effect of treatment accounted for repeated measurements and tested potential interaction with baseline permeability, HbA(1c), and arterial blood pressure. RESULTS: Statistical analysis and modeling demonstrated a significant interaction between RBX treatment at any dosage and baseline permeability (P = 0.032, mixed models). A threefold or higher increase in retinal vascular leakage at baseline was associated with a significant reduction (30%) in retinal vascular leakage after RBX treatment compared with placebo. Visual acuity was normal at baseline and remained unchanged throughout the study. CONCLUSIONS: RBX treatment was associated with a reduction of retinal vascular leakage in eyes that had diabetic macular edema and markedly elevated leakage at baseline. These data suggest that clinical benefit from RBX treatment may be most prominent in patients with severe macular edema at baseline, and trials investigating this therapy may benefit from stratification according to baseline leakage.

Administration, Oral↗
PubMed2004

Risks of intravitreous injection: a comprehensive review.

PURPOSE: To evaluate the prevalence of the most common serious adverse events associated with intravitreous (IVT) injection. METHODS: A systematic search of the literature via PubMed from 1966 to March 1, 2004, was conducted to identify studies evaluating the safety of IVT injection. Data submitted in New Drug Applications to the U.S. Food and Drug Administration for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were recorded, and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Rare complications also were noted. RESULTS: Data from 14,866 IVT injections in 4,382 eyes were analyzed. There were 38 cases of endophthalmitis (including those reported as pseudoendophthalmitis) for a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophthalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with IVT injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were described rarely in patients after IVT injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations. CONCLUSION: The risk of serious adverse events reported after IVT injection is low. Nevertheless, careful attention to injection technique and appropriate postinjection monitoring are essential because uncommon injection-related complications may be associated with permanent vision loss.

Cataract↗
PubMed2004

Bifunctional properties of peroxisome proliferator-activated receptor gamma1 in KDR gene regulation mediated via interaction with both Sp1 and Sp3.

Vascular endothelial growth factor receptor 2 (KDR) plays a critical role in mediating a variety of vasculogenic and angiogenic processes, including diabetic retinopathy. We previously demonstrated that the promoter activity of the KDR gene in retinal capillary endothelial cells (RCECs) was regulated in part by the relative concentration of positive/negative transcription factors Sp1/Sp3. We also reported that the peroxisome proliferator-activated receptor (PPAR)gamma ligand could inhibit intraocular angiogenesis. In the present study, the role of PPARgamma1 in KDR gene regulation in RCECs was examined. PPARgamma1 protein physically interacted with both Sp1 and Sp3. Transactivation and electrophoretic mobility shift assays clearly demonstrated novel findings that PPARgamma1 increased KDR promoter activity by enhancing the interaction between Sp1, but not Sp3, and KDR promoter region without its ligand in RCECs. The ligand-binding site but not the DNA binding site of PPARgamma1 enhanced the interaction between Sp1 and KDR promoter region. Conversely, PPARgamma1 ligand 15-deoxy Delta (12,14)-prostaglandin J2 dose-dependently suppressed the binding of KDR promoter region with both Sp1 and Sp3, resulting an inhibition of KDR gene expression. In conclusion, PPARgamma1 has bifunctional properties in the regulation of KDR gene expression mediated via interaction with both Sp1 and Sp3.

Animals↗
PubMed2003

Use of Joslin Vision Network digital-video nonmydriatic retinal imaging to assess diabetic retinopathy in a clinical program.

PURPOSE: To incorporate a nonmydriatic, digital-video retinal imaging system into a Diabetes Outpatient Intensive Treatment Program and to evaluate the system's ability to assess diabetic retinopathy (DR), determine follow-up, and appropriately refer to retinal specialist ophthalmologists. METHODS: Fundus images were obtained according to Joslin Vision Network (JVN) protocol and evaluated by certified JVN readers. Patients with significant retinal disease underwent evaluation by retinal specialists. RESULTS: A total of 268 (51.0%) of 525 imaged patients had comprehensive eye examination by a retinal specialist owing to referable JVN-assessed clinical level of DR, nondiabetic ocular disease, ungradeable images, last eye examination >/=12 months prior, or patient request for examination. JVN diagnosis of a clinical level of DR agreed exactly with clinical findings in 388 eyes (72.5%) or within one level in 478 eyes (89.3%). JVN referral based on most severe diagnosis in either eye matched retinal specialist-recommended follow-up in 248/268 of patients (92.5%). A total of 136/525 (25.9%) of JVN patients had nondiabetic ocular abnormalities requiring referral. CONCLUSIONS: Recommended follow-up from JVN imaging compared favorably to clinical examination by a retinal specialist. Nondiabetic ocular pathology was identified. JVN assessment of DR level compares favorably to clinical practice, potentially improving access to eye care and enhancing diabetes management.

Adolescent↗
PubMed2002

Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes.

Diabetic macular edema, resulting from increased microvascular permeability, is the most prevalent cause of vision loss in diabetes. The mechanisms underlying this complication remain poorly understood. In the current study, diabetic vascular permeability (blood-retinal barrier breakdown) is demonstrated to result from a leukocyte-mediated Fas-FasL-dependent apoptosis of the retinal vasculature. Following the onset of streptozotocin-induced diabetes, FasL expression was increased in rat neutrophils (P<0.005) and was accompanied by a simultaneous increase in Fas expression in the retinal vasculature. Static adhesion assays demonstrated that neutrophils from diabetic, but not control, rats induced endothelial cell apoptosis in vitro (P<0.005). The latter was inhibited via an antibody-based FasL blockade (P<0.005). In vivo, the inhibition of FasL potently reduced retinal vascular endothelial cell injury, apoptosis, and blood-retinal barrier breakdown (P<0.0001) but did not diminish leukocyte adhesion to the diabetic retinal vasculature. Taken together, these data are the first to identify leukocyte-mediated Fas-FasL-dependent retinal endothelial cell apoptosis as a major cause of blood-retinal barrier breakdown in early diabetes. These data imply that the targeting of the Fas-FasL pathway may prove beneficial in the treatment of diabetic retinopathy.

Animals↗
PubMed2002

Characterization of protein kinase C beta isoform's action on retinoblastoma protein phosphorylation, vascular endothelial growth factor-induced endothelial cell proliferation, and retinal neovascularization.

Retinal neovascularization is a major cause of blindness and requires the activities of several signaling pathways and multiple cytokines. Activation of protein kinase C (PKC) enhances the angiogenic process and is involved in the signaling of vascular endothelial growth factor (VEGF). We have demonstrated a dramatic increase in the angiogenic response to oxygen-induced retinal ischemia in transgenic mice overexpressing PKC beta 2 isoform and a significant decrease in retinal neovascularization in PKC beta isoform null mice. The mitogenic action of VEGF, a potent hypoxia-induced angiogenic factor, was increased by 2-fold in retinal endothelial cells by the overexpression of PKC beta 1 or beta 2 isoforms and inhibited significantly by the overexpression of a dominant-negative PKC beta 2 isoform but not by the expression of PKC alpha, delta, and zeta isoforms. Association of PKC beta 2 isoform with retinoblastoma protein was discovered in retinal endothelial cells, and PKC beta 2 isoform increased retinoblastoma phosphorylation under basal and VEGF-stimulated conditions. The potential functional consequences of PKC beta-induced retinoblastoma phosphorylation could include enhanced E2 promoter binding factor transcriptional activity and increased VEGF-induced endothelial cell proliferation.

Animals↗
PubMed2002

Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue.

BACKGROUND: Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states. Methods and Results- The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes. CONCLUSIONS: The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.

Animals↗