title: cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants.
abstract: Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP) has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE) with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2) for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation) mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities) and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions.
authors.affiliation: Grupo de Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Olivares-González
authors.affiliation: Grupo de Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Martínez-Fernández de la Cámara
authors.affiliation: Unidad de Bioestadística, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Hervás
authors.affiliation: Unidad de Microscopía, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Marín
authors.affiliation: Unidad de Hepatología Experimental, Unidad Analítica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
authors.forename: Agustin
authors.initials: A
authors.lastname: Lahoz
authors.affiliation: Grupo de Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Millán
authors.affiliation: Grupo de Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.|CIBER de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Regina
authors.identifier: http://orcid.org/0000-0001-5875-986X
authors.initials: R
authors.lastname: Rodrigo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013552:Swine; D046509:Tissue Culture Techniques
chemical_list: D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010726:Phosphodiesterase Inhibitors; D013481:Superoxides; D019344:Lactic Acid; D019289:Pyruvic Acid; D011065:Poly(ADP-ribose) Polymerases; D010727:Phosphoric Diester Hydrolases; D053148:Caspase 3; D006152:Cyclic GMP