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1.
Cell Metab ; 33(4): 818-832.e7, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33548171

RESUMEN

Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.


Asunto(s)
Senescencia Celular , Enfermedades de la Retina/patología , Proteína bcl-X/metabolismo , Animales , Apoptosis/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Flavonoles/química , Flavonoles/farmacología , Flavonoles/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Patológica , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/metabolismo , Tacrolimus/análogos & derivados , Tacrolimus/farmacología , Proteína bcl-X/antagonistas & inhibidores
2.
Nat Rev Drug Discov ; 16(10): 718-735, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28729727

RESUMEN

Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.


Asunto(s)
Envejecimiento/patología , Envejecimiento/fisiología , Proliferación Celular/fisiología , Senescencia Celular/fisiología , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Puntos de Control del Ciclo Celular/fisiología , Humanos , Neoplasias/metabolismo , Neoplasias/patología
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