Complement Mediators in Development to Treat Age-Related Macular Degeneration

Nebbioso, Marcella; Franzone, Federica; Lambìase, Alessandro; Taurone, Samanta; Artico, Marco; Gharbiya, Magda; Greco, Antonio; Polimeni, Antonella

doi:10.1007/s40266-021-00914-x

Cited by 3 publications

(2 citation statements)

References 80 publications

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“…The delineation of this pathway could facilitate the development of diagnostic, preventive, or therapeutic treatment strategies. Vitronectin has been recognized previously as a promising therapeutic target to regulate complement activation and inflammation [ 111 ] and to prevent ectopic deposits associated with AMD [ 19 ]. Addressing the need to regulate and not simply inhibit pathological angiogenic events in NV-AMD [ 112 ], therapeutic modulation of vitronectin and PAI-1 protein expression, either through genetic or pharmacological approaches, could contribute to the restoration of vascular homeostasis and, thus, help to prevent or treat vascular abnormalities in late stage AMD.…”

Section: Discussionmentioning

confidence: 99%

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

Biasella

Strunz

Kiel

et al. 2022

Cells

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The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD.

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Section: Discussionmentioning

confidence: 99%

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

Biasella

Strunz

Kiel

et al. 2022

Cells

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“…Neovascular membranes respond to anti vascular endothelial growth factor (VEGF) therapy, while this treatment is useless in dry AMD. In this case, the only available treatment today consists of a specific combination of substances according to the Age-Related Eye Disease Study (AREDS 1 and 2) for the prevention of disease progression [ 21 , 23 , 24 , 25 ].…”

Section: Major Retinal Diseases and Oxidative/nitrosative Stressmentioning

confidence: 99%

Oxidative Stress Implication in Retinal Diseases—A Review

et al. 2022

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Oxidative stress (OS) refers to an imbalance between free radicals (FRs), namely highly reactive molecules normally generated in our body by several pathways, and intrinsic antioxidant capacity. When FR levels overwhelm intrinsic antioxidant defenses, OS occurs, inducing a series of downstream chemical reactions. Both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced by numerous chemical reactions that take place in tissues and organs and are then eliminated by antioxidant molecules. In particular, the scientific literature focuses more on ROS participation in the pathogenesis of diseases than on the role played by RNS. By its very nature, the eye is highly exposed to ultraviolet radiation (UVR), which is directly responsible for increased OS. In this review, we aimed to focus on the retinal damage caused by ROS/RNS and the related retinal pathologies. A deeper understanding of the role of oxidative and nitrosative stress in retinal damage is needed in order to develop targeted therapeutic interventions to slow these pathologies.

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