Inflammation and the pathogenesis of age-related macular degeneration

Augustin, Albert J.; Kirchhof, Janna

doi:10.1517/14728220902942322

Cited by 72 publications

(50 citation statements)

References 48 publications

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“…Inflammation and angiogenesis play pivotal roles in CNV, the major cause of vision loss in patients with AMD (39,40). Our results show that miR-23∼27∼24 cluster members are up-regulated in CNV (Fig.…”

Section: Discussionmentioning

confidence: 56%

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Zhou¹,

Gallagher²,

Ufret-Vincenty³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

316

287

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MicroRNAs (miRNAs) modulate complex physiological and pathological processes by repressing expression of multiple components of cellular regulatory networks. Here we demonstrate that miRNAs encoded by the miR-23∼27∼24 gene clusters are enriched in endothelial cells and highly vascularized tissues. Inhibition of miR-23 and miR-27 function by locked nucleic acid-modified anti-miRNAs represses angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, miR-23 and miR-27 are required for pathological angiogenesis in a laser-induced choroidal neovascularization mouse model. MiR-23 and miR-27 enhance angiogenesis by promoting angiogenic signaling through targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity. Manipulating miR-23/ 27 levels may have important therapeutic implications in neovascular age-related macular degeneration and other vascular disorders.blindness | MAP kinase signaling | semaphorins | Akt | proangiogenic T he growth of blood vessels through angiogenesis is a delicately controlled process that involves endothelial cell (EC) activation, proliferation, migration, and maturation (1). Physiological angiogenesis is required for normal vascular development as well as vascular homeostasis during adulthood. Pathological angiogenesis, commonly induced by tissue ischemia or inflammation, underlies numerous vascular disorders, such as age-related macular degeneration (AMD), a leading cause of blindness in the elderly (2). Choroidal neovascularization (CNV), which involves abnormal growth of blood vessels in the back of the eye, is a hallmark of neovascular AMD (3). Although the pathogenic mechanisms underlying AMD are still largely unknown, vascular endothelial growth factor (VEGF) has been shown to play a causal role in the development of CNV (4). Anti-VEGF agents have demonstrated efficacy in treating CNV in neovascular AMD (5, 6) but have limited efficacy and potential side effects (7,8).Recent studies have revealed important roles for microRNAs (miRNAs) in cardiovascular diseases and other disorders (9). miRNAs are small noncoding RNAs that negatively regulate gene expression by inducing mRNA degradation or inhibiting translation through binding to the 3′ untranslated region (3′UTR) of target mRNAs (10). Often, miRNAs modulate broad collections of mRNAs encoding multiple components of complex biological pathways. Several miRNAs have been implicated in angiogenesis (11,12). A group of miRNAs has also been shown to be substantially decreased in a laser-induced CNV model (13).The miR-23∼27∼24 clusters are highly expressed in ECs (14-17). Two miR-23∼27∼24 clusters exist in the vertebrate genome: an intergenic miR-23a∼27a∼24-2 cluster and an intronic miR23b∼27b∼24-1 cluster. Members of these clusters are involved in cell cycle control, proliferation, and differentiation of various cell types (18). Here, we show that inhibition of miR-23/27 impairs angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, silencing of miR-23/27 suppresses l...

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Section: Discussionmentioning

confidence: 56%

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Zhou¹,

Gallagher²,

Ufret-Vincenty³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

316

287

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“…The role of inflammation has been given much consideration [20], even if the nature of the immune cell interactions that drive cellular and tissue changes in AMD is still not fully understood [21]. …”

Section: Discussionmentioning

confidence: 99%

Hyperreflective Dots: A New Spectral-Domain Optical Coherence Tomography Entity for Follow-Up and Prognosis in Exudative Age-Related Macular Degeneration

et al. 2012

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Purpose: Spectral-domain optical coherence tomography (SD-OCT) enables high-resolution analysis of retinal layers and previously unseen hyperreflective dots (HRD). HRD morphological characteristics, evolution, possible origin and prognostic value are discussed. Methods: We conducted a prospective study of 100 patients with exudative age-related macular degeneration (AMD), who were treated and followed up with monthly imaging examinations. Statistical correlations between visual acuity (VA) and pre-/post- treatment HRD characteristics were evaluated. Results: HRD were present in all cases, mainly in the outer retinal layers but also elsewhere. After treatment, HRD regressed in a few days, 1 month (p < 0.04) and 3 months (p < 0.01). Regression was evident in all VA and morphological subsets. Resolution was associated with better final VA (p < 0.001). Conclusions: Presence of initial/recurrent HRD, rapid treatment response and the growing role that early biological inflammatory reaction plays in AMD suggests HRD are activated microglia cells. The correlation between VA and HRD could make HRD a clinical marker for early decisions about treatment and retreatment.

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“…33 Dramatic advances have been made in unraveling the biological bases of AMD, implicating chronic local inflammation and activation of the complement cascade in the pathogenesis of the condition. 16,17 A number of complement system proteins, complement activators and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD 12,[39][40][41][42] and of geographic atrophy and choroidal neovascularization, the hallmark of advanced AMD. 43 Genetic studies revealed highly significant associations between AMD and variants of several complement pathway-associated genes, including complement factor H, complement factor H-related 1 and 3, complement factor B, complement component 2 and complement component 3.…”

Section: Discussionmentioning

confidence: 99%

“…10 Inflammation has recently received some attention as a potential risk factor for AMD. [11][12][13][14][15][16][17][18][19][20][21][22] Immunological changes seemed to be related to early pathological changes in retinal pigment epithelial (RPE) and drusen formation. Immune components, including immunoglobulins, complement factors and fibrinogen, have been observed to be entrapped within drusen.…”

Section: Introductionmentioning

confidence: 99%

Reconsidering the connection between vitamin D levels and age-related macular degeneration

Golan

Shalev

Treister

et al. 2011

Eye

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Inflammation and the pathogenesis of age-related macular degeneration

Abstract: It is now well-known that AMD is a multi-factorial disease, with environmental causes and genetics all playing a role.

Cited by 72 publications

References 48 publications

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters

Hyperreflective Dots: A New Spectral-Domain Optical Coherence Tomography Entity for Follow-Up and Prognosis in Exudative Age-Related Macular Degeneration

Reconsidering the connection between vitamin D levels and age-related macular degeneration

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