scholarly journals The Protective Effects of Endogenous PACAP in Oxygen-induced Retinopathy 

2021 ◽  
Author(s):  
Timea Kvarik ◽  
Dora Werling ◽  
Alexandra Vaczy ◽  
Petra Kovari ◽  
Edina Szabo ◽  
...  
Keyword(s):  
Protein Kinase B ◽  
Protective Effects ◽  
Wild Type ◽  
Avascular Area ◽  
Oxygen Induced Retinopathy ◽  
Angiogenic Proteins ◽  
Pituitary Adenylate Cyclase ◽  
Neural Tissues ◽  
Retinal Structure ◽  
Deficient Mice

Abstract Purpose: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide having trophic and protective functions in neural tissues including the retina. Previously we have shown that intravitreal PACAP administration can maintain retinal structure in the animal model of retinopathy of prematurity (ROP). The purpose of this study is to examine the development of ROP in PACAP-deficient and wild-type mice to reveal the function of endogenous PACAP. Methods: Wild-type and PACAP-KO mouse pups at postnatal day (PD) 7 were maintained at 80% oxygen for 5 consecutive days then returned to room air on PD12 to develop oxygen-induced retinopathy (OIR). On PD15 animals underwent electroretinography (ERG) to assess visual function. On PD16 eyes were harvested for either immunohistochemistry to determine the percentage of central avascular retinal area and neovascular tuft formation or molecular analysis to assess angiogenesis proteins by array kit and antiapoptotic protein kinase B (Akt) change by western blot. Results: The retina of PACAP deficient OIR mice showed greater central avascular area than that of the wild types. ERG revealed significantly decreased b-wave amplitude in PACAP KO compared to their controls. Several angiogenic proteins were upregulated as a results of OIR and 11 further proteins markedly increased in PACAP deficient mice. Conclusion: This is the first study to examine the endogenous effect of PACAP in OIR model. Previously we have shown the beneficial effect of exogenous local PACAP treatment in the rat OIR model. Together with the present findings we suppose that PACAP could be a novel retinoprotective agent in ROP.

scholarly journals The Protective Effects of Endogenous PACAP in Oxygen-Induced Retinopathy

2021 ◽  
Author(s):  
Timea Kvarik ◽  
Dora Reglodi ◽  
Dora Werling ◽  
Alexandra Vaczy ◽  
Petra Kovari ◽  
...  
Keyword(s):  
Western Blot ◽  
Protective Effects ◽  
Wild Type ◽  
Avascular Area ◽  
Akt Phosphorylation ◽  
Oxygen Induced Retinopathy ◽  
Apoptotic Protein ◽  
Angiogenic Proteins ◽  
Pituitary Adenylate Cyclase ◽  
Retinal Structure

AbstractPituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide having trophic and protective functions in neural tissues, including the retina. Previously, we have shown that intravitreal PACAP administration can maintain retinal structure in the animal model of retinopathy of prematurity (ROP). The purpose of this study is to examine the development of ROP in PACAP-deficient and wild-type mice to reveal the function of endogenous PACAP. Wild-type and PACAP-knockout (KO) mouse pups at postnatal day (PD) 7 were maintained at 75% oxygen for 5 consecutive days then returned to room air on PD12 to develop oxygen-induced retinopathy (OIR). On PD15, animals underwent electroretinography (ERG) to assess visual function. On PD16, eyes were harvested for either immunohistochemistry to determine the percentage of the central avascular retinal area or molecular analysis to assess angiogenesis proteins by array kit and anti-apoptotic protein kinase B (Akt) change by western blot. Retinas of PACAP-deficient OIR mice showed a greater central avascular area than that of the wild types. ERG revealed significantly decreased b-wave amplitude in PACAP KO compared to their controls. Several angiogenic proteins were upregulated due to OIR, and 11 different proteins markedly increased in PACAP-deficient mice, whereas western blot analysis revealed a reduction in Akt phosphorylation, suggesting an advanced cell death in the lack of PACAP. This is the first study to examine the endogenous effect of PACAP in the OIR model. Previously, we have shown the beneficial effect of exogenous local PACAP treatment in the rat OIR model. Together with the present findings, we suggest that PACAP could be a novel retinoprotective agent in ROP.

Abstract 1493: Erythropoietin Stimulates Endothelial Biosynthesis of Tetrahydrobiopterin by Activation of Phosphatidylinositol 3-kinase/Protein Kinase B Signal Transduction Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Livius V d’Uscio ◽  
Anantha V Santhanam ◽  
Zvonimir S Katusic
Keyword(s):  
Protein Kinase ◽  
Enzymatic Activity ◽  
Vascular Endothelium ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Protein Kinase B ◽  
Wild Type Mouse ◽  
Protective Effects ◽  
Wild Type ◽  
Deficient Mice

Erythropoietin (EPO) has been recognized as a tissue protective cytokine. Recently, it has been shown that vascular protective effects of EPO are dependent on activation of endothelial nitric oxide synthase (eNOS). Tetrahydrobiopterin (BH 4 ) is an essential cofactor required for enzymatic activity of eNOS. Therefore, our objective was to characterize the effect of EPO on biosynthesis of BH 4 in vascular wall. Incubation of isolated wild-type (C57BL/6J) mouse aortas for 18 hours at 37°C in minimal essential medium supplemented with recombinant human EPO (1–50 U/ml) caused concentration-dependent increase in intracellular levels of BH 4 as determined by HPLC analysis. Maximum biosynthesis of BH 4 was detected at therapeutic concentrations of 5 U/mL (15.8±1.3 pmol/mg protein; P<0.05 vs control: 8.2±0.4 pmol/mg protein; n=6 – 8). Oxidative products of BH 4 , 7,8-dihydrobiopterin, were unaffected by EPO indicating that EPO does not affect oxidation of BH 4 . Removal of the endothelium abolished EPO-induced biosynthesis of BH 4 (P<0.05; n=5) demonstrating that the vascular endothelium is a major source of BH 4 . Treatment of intact isolated wild-type mouse aortas with a selective phosphatidylinositol (PI)3-kinase inhibitor wortmannin (1 μM) significantly reduced BH 4 biosynthesis by EPO (8.4±0.6 pmol/mg protein; P<0.05; n=6). Stimulatory effect of EPO on production of BH 4 in aorta was also detected in wild-type mice treated with recombinant human EPO (1000 U/kg, s.c. biweekly) for 14 days (P<0.05; n=6). This vascular effect was abolished in protein kinase B (Akt) 1-deficient mice treated with EPO (P<0.05; n=5). Furthermore, aortic GTP cyclohydrolase I (GTPCH I) enzymatic activity was augmented in EPO treated wild-type mice (0.48±0.12 pmol neopterin/mg protein; P<0.05 vs control: 0.23±0.05 pmol neopterin/mg; n=4) but not in EPO treated Akt 1-deficient mice (0.21±0.03 pmol neopterin/mg; n=4), indicating that the selective increase in BH 4 levels was caused by de-novo biosynthesis of BH 4 via Akt/GTPCH I pathway. Our results demonstrate that EPO stimulates biosynthesis of BH 4 in vascular endothelium. This effect is most likely designed to provide optimal intracellular concentration of cofactor necessary for EPO-induced elevation of eNOS activity.

scholarly journals Protective Role of Endogenous PACAP in Inflammation-induced Retinal Degeneration

2018 ◽  
Vol 24 (30) ◽  
pp. 3534-3542 ◽  
Author(s):  
Alexandra Vaczy ◽  
Petra Kovari ◽  
Krisztina Kovacs ◽  
Kinga Farkas ◽  
Edina Szabo ◽  
...  
Keyword(s):  
Protective Role ◽  
Protective Effects ◽  
Wild Type ◽  
Retinal Degenerations ◽  
Enhanced Sensitivity ◽  
Functional Differences ◽  
Pituitary Adenylate Cyclase ◽  
Retinal Inflammation ◽  
Lps Treatment

Purpose: Pituitary adenylate Cyclase-Activating Polypeptide (PACAP) is a neuroprotective peptide that has been shown to exert protective effects in different models of neurodegenerative diseases, including retinal degenerations. Data obtained from PACAP-deficient (PACAP KO) mice provide evidence that endogenous PACAP has a neuroprotective role in different pathologies. PACAP KO mice show enhanced sensitivity to different insults, such as oxidative stress, hypoxia and inflammation. The aim of the present study was to investigate the protective effects of endogenous PACAP in retinal inflammation. Methods: Endotoxin-induced eye inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS) in PACAP KO and wild-type (Wt) mice. After LPS treatment, retinas were processed for histological examination. To detect the alterations of different proteins and cytokines, immunohistochemical, western blot and cytokine array were used. We also performed dark-adapted electroretinography (ERG) to detect the functional differences. Results: The thickness of nearly all layers was significantly less in LPS-injected PACAP KO mice compared to Wt animals. Increased expression of Glial Fibrillary Acidic Protein (GFAP) was induced in Müller glial cells after LPS treatment, which was more intense in PACAP KO mice. The levels of pAkt and pGSK were decreased in PACAP KO group during inflammation. LPS treatment significantly increased cytokines (sICAM-1, JE, TIMP-1) in both treated groups, but it was more expressed in PACAP KO animals. Furthermore, ERG responses were disturbed after LPS injection in PACAP KO mice. Conclusion: Our results showed that endogenous PACAP has a protective role in LPS-caused retinal inflammation.

Different effects of chronic helicobactor pylori infection on parietal and ECL cells between wild type and gastrin-deficient mice

2001 ◽  
Vol 120 (5) ◽  
pp. A728-A728
Author(s):  
D CHEN ◽  
L FRIISHANSEN ◽  
X WANG ◽  
C ZHAO ◽  
H WALDUM ◽  
...  
Keyword(s):  
Wild Type ◽  
Ecl Cells ◽  
Helicobactor Pylori ◽  
Deficient Mice

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1379
Author(s):  
Dongjoon Kim ◽  
Hiromi Sesaki ◽  
Sayon Roy
Keyword(s):  
Diabetic Retinopathy ◽  
Cell Loss ◽  
Vascular Lesions ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Wild Type ◽  
Apoptotic Genes ◽  
Retinal Vascular Lesions ◽  
Acellular Capillaries ◽  
Pericyte Loss

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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