endothelin-1 and Retinitis-Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death. The purposes of this study were: 1) to analyze the temporal profile of HIF-1α, its downstream effectors VEGF, endothelin-1 (ET-1), iNOS, and glucose transporter 1 (GLUT1), and neuroinflammation in retinas of the murine model of rd10 ( retinal degeneration 10) mice with RP; 2) to study oxygen bioavailability in these retinas; and 3) to investigate how stabilizing HIF-1α proteins with dimethyloxaloglycine (DMOG), a prolyl hydroxylase inhibitor, affects retinal degeneration, neuroinflammation, and antioxidant response in rd10 mice. A generalized down-regulation of HIF-1α and its downstream targets was detected in parallel with reactive gliosis, suggesting high oxygen levels during retinal degeneration. At postnatal d 18, DMOG treatment reduced photoreceptor cell death and glial activation. In summary, retinas of rd10 mice seem to be exposed to a hyperoxic environment even at early stages of degeneration. HIF-1α stabilization could have a temporal neuroprotective effect on photoreceptor cell survival, glial activation, and antioxidant response at early stages of RP.-Olivares-González, L., Martínez-Fernández de la Cámara, C., Hervás, D., Millán, J. M., Rodrigo, R. HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

Topics: Amino Acids, Dicarboxylic; Animals; Cell Survival; Disease Models, Animal; Down-Regulation; Endothelin-1; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Mutant Strains; Nitric Oxide Synthase Type II; Protein Stability; Retina; Retinitis Pigmentosa; Vascular Endothelial Growth Factor A

Endothelin-1 is a strong endogenous vasoconstrictor and is also an agent reducing the ocular blood flow. Patients with retinitis pigmentosa are known to have reduced ocular blood flow. This can be secondary to retinal atrophy, but may also partially result from an additional condition, such as a Flammer syndrome. The aim of the study was to investigate whether the endothelin-1 plasma levels in retinitis pigmentosa patients with and without Flammer syndrome are different.. In the study we included patients with clinical signs and symptoms of retinitis pigmentosa, confirmed by electrophysiological findings. Blood samples were obtained from 6 retinitis pigmentosa patients with and 4 without Flammer syndrome. The results were related to 30 age- and sex-matched control subjects. Endothelin-1 plasma levels were determined by specific radioimmunoassay.. The endothelin-1 plasma levels in retinitis pigmentosa patients with Flammer syndrome were significantly higher than those without Flammer syndrome. The mean (±SD) endothelin-1 levels (pg/mL) in retinitis pigmentosa patients with Flammer syndrome were 4.95 (±1.74), range: (2.37-6.76), whereas in patients without Flammer syndrome they were 1.10 (±0.08), range: 1.00-1.20. Our own normal values are: 1.56 (±0.30), range: (0.90-2.13). All retinitis pigmentosa patients with increased endothelin-1 plasma levels had signs and symptoms related to a Flammer syndrome, such as cold extremities, low blood pressure, reduced feeling of thirst, increased sensitivity in general, e.g., increased sensitivity to certain drugs, increased pain sensitivity and increased sense of smell.. Endothelin-1 plasma levels were increased in retinitis pigmentosa patients with but not in patients without Flammer syndrome. Many questions remain open: Why so many retinitis pigmentosa patients suffer from Flammer syndrome, why is the endothelin-1 level in such patients higher than in healthy subjects with Flammer syndrome, how much of the ocular blood flow reduction is due to retinal degeneration and how much to the Flammer syndrome? We hypothesise that Flammer syndrome leads to an additional increase of the endothelin-1 level and an additional decrease of ocular blood flow in retinitis pigmentosa patients. Further studies are needed to analyse the causal relationship between retinitis pigmentosa and Flammer syndrome and evaluate potential therapeutic implications.

Topics: Adult; Biomarkers; Diagnosis, Differential; Endothelin-1; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Reproducibility of Results; Retinitis Pigmentosa; Sensitivity and Specificity; Syndrome

To assess the relationship between both photoreceptor function and choroidal thickness and endothelin-1 (ET-1) plasma levels in patients with early stage retinitis pigmentosa (RP).. We compared 24 RP patients (14 males and 10 females), 25 to 42 years of age (mean age: 34±7 years) with 24 healthy controls (12 males and 12 females) aged between 28 and 45 years (mean 36±6.8 years). All patients underwent visual field test, electroretinogram and multifocal-electroretinogram and choroidal thickness measurement by using spectral domain optical coherence tomography.. RP patients had a visual acuity of 0.95, a mean defect of the visual field of -7.90±1.75 dB, a pattern standard deviation index of 6.09±4.22 dB and a b-wave ERG amplitude of 45.08±8.24 μV. Notably RP subjects showed significantly increased ET-1 plasma levels and reduced choroidal thickness compared with controls: respectively, 2.143±0.258 pg/ml vs. 1.219±0.236 pg/ml; p<0.002 and 226.75±76.37 μm vs. 303.9±39.87 μm; p<0.03. Spearman's correlation test highlighted that the increase of ET-1 plasma levels was related with the decrease of choroidal thickness (r=-0.702; p<0.023) and the increase of implicit time in both ring 2 (r=-0.669; p<0.034) and ring 3 (r=-0.883; p<0.007) of mfERG.. Increased ET-1 plasma levels may play a key role in the impairment of retinal and choroidal blood flow due to the vasoconstriction induced by ET-1. This could lead to worsening of the abiotrophic process of the macular photoreceptors.

Topics: Adult; Case-Control Studies; Choroid; Demography; Electroretinography; Endothelin-1; Female; Humans; Male; Retinitis Pigmentosa; Tomography, Optical Coherence

The aim of this study was to investigate the behaviour of plasma endothelin-1 (ET-1) levels in patients affected by retinitis pigmentosa (RP) and syndromic RP.. Blood samples were obtained from a group of 40 consecutive patients with RP matched with 35 healthy subjects (HS) as control. We carried out a complete ophthalmological examination. The study group included 26 patients with RP and 14 patients with syndromic RP. Plasma ET-1 levels were determined in duplicate with a specific radioimmunoassay method.. In the HS plasma ET-1 levels were 7.48+/-2.58 pg/mL. The mean of plasma ET-1 concentrations in all patients with RP ( 16.2+/-5.6 pg/mL) was significantly (P<0.01) higher than that of HS. Moreover, in the syndromic RP patients, plasma ET-1 levels (18.9+/-6.8 pg/mL) were higher than those of HS and RP patients (P<0.01).. The increase of plasma ET-1 levels in RP patients suggests that ET-1 may play a role in the pathophysiology of the diseases involving retinal pigment epithelial cells and the retinal vascular system such as RP.

Topics: Adult; Endothelin-1; Female; Humans; Male; Middle Aged; Radioimmunoassay; Retinitis Pigmentosa

Retinitis pigmentosa (RP) is an inherited retinal disorder clinically characterized by a pale, waxy optic nerve head, attenuated retinal blood vessels, and bone spicule pigment in the retina. Hemodynamic studies have demonstrated that RP is associated with a reduction in the retinal and choroidal blood flow. Retinal hemodynamic impairment is also present in early stages of RP, and various hypotheses have been advanced as to the cause. The authors studied 20 patients, 12 males and 8 females, aged 26-42 years (mean 35.1 years) and affected by simplex RP. The patients had a visual acuity of 0.9 +/- 0.1, visual field mean defect of -6.52 +/- 3.58 dB, and b-wave electroretinogram amplitude of 260.08 +/- 8.24 microV. An increase in plasma levels of endothelin-1 (ET-1) was found: 1.910 +/- 0.317 pg/mL versus 1.180 +/- 0.210 pg/mL in non-RP controls (p < 0.02). Moreover both an ocular and systemic vascular impairment was detected by means of color Doppler imaging and laser Doppler flowmetry performed during a cold pressor test. We found a correlation between the increase of ET-1 plasma levels in RP and the decrease of peak systolic velocity in the ophthalmic artery (p < 0.03) and in the posterior ciliary arteries (p < 0.006). It is thought that an increase of ET-1 and retinal oxygen levels in RP could lead to vasoconstriction and a decrease of the retinal blood flow, worsening the abiotrophic process.

Topics: Adult; Body Temperature; Capillaries; Ciliary Arteries; Endothelin-1; Eye; Female; Humans; Laser-Doppler Flowmetry; Male; Ophthalmic Artery; Regional Blood Flow; Retinitis Pigmentosa; Skin; Ultrasonography, Doppler, Color