RESUMO
This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca2+)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using Western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.
Assuntos
Papiledema , Doenças Retinianas , Canais de Potencial de Receptor Transitório , Doenças Vasculares , Camundongos , Humanos , Animais , Permeabilidade Capilar , Canais de Cátion TRPV/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/farmacologia , Células Endoteliais/metabolismo , Papiledema/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Doenças Retinianas/metabolismo , Doenças Vasculares/metabolismoAssuntos
Colo Sigmoide/diagnóstico por imagem , Doença Diverticular do Colo/diagnóstico por imagem , Fístula Intestinal/diagnóstico por imagem , Colo Sigmoide/cirurgia , Colonoscopia , Diagnóstico Diferencial , Doença Diverticular do Colo/cirurgia , Humanos , Fístula Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of alpha-Fas-induced liver injury.
Assuntos
Inibidores de Caspase , Inibidores de Cisteína Proteinase/síntese química , Hepatopatias/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Células Jurkat , Camundongos , Relação Estrutura-Atividade , Receptor fasRESUMO
In a mouse model of alpha-Fas-induced acute liver injury, the orally-administered caspase inhibitor PF-03491390 (formerly named IDN-6556) was retained in the liver for prolonged periods with a low systemic exposure. Reductions in the elevated plasma levels of alanine aminotransferase (ALT) revealed that the retention of PF-03491390 in the liver exerted a hepatoprotective effect, even when pre-administered to mice 4 h before alpha-Fas insult. Prolonged retention of PF-03491390 in the liver after oral administration has the benefit of low systemic exposure, making this a beneficial agent for the treatment of liver diseases.