The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

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Abstract

Understanding the mechanisms that underlie age-related macular degeneration (AMD) has led to the identification of key molecules. Hypoxia-inducible transcription factors (HIFs) have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of nAMD. This knowledge has propelled the development of a new group of therapeutic strategies focused on gene therapy. The present review provides an update on current gene therapies in ocular angiogenesis, particularly nAMD, from both basic and clinical perspectives.

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Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

Weibo Luo, Hongxia Hu, Ryan Chang … (2011)

The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.

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Endothelial cell migration during angiogenesis.

Laurent Lamalice, Fabrice Le Boeuf, Jacques Huot (2007)

Endothelial cell migration is essential to angiogenesis. This motile process is directionally regulated by chemotactic, haptotactic, and mechanotactic stimuli and further involves degradation of the extracellular matrix to enable progression of the migrating cells. It requires the activation of several signaling pathways that converge on cytoskeletal remodeling. Then, it follows a series of events in which the endothelial cells extend, contract, and throw their rear toward the front and progress forward. The aim of this review is to give an integrative view of the signaling mechanisms that govern endothelial cell migration in the context of angiogenesis.

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Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

John W. Crabb, Masaru Miyagi, Xiaorong GU … (2002)

Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.

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Author and article information

Contributors

Helder André: helder.andre@ki.se

Journal

Journal ID (nlm-ta): Cell Mol Life Sci

Journal ID (iso-abbrev): Cell. Mol. Life Sci

Title: Cellular and Molecular Life Sciences

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1420-682X

ISSN (Electronic): 1420-9071

Publication date (Electronic): 31 December 2019

Publication date PMC-release: 31 December 2019

Publication date (Print): 2020

Volume: 77

Issue: 5

Pages: 819-833

Affiliations

GRID grid.416386.e, ISNI 0000 0004 0624 1470, Division of Eye and Vision, Department of Clinical Neuroscience, Karolinska Institutet, , St. Erik Eye Hospital, ; Stockholm, Sweden

Article

Publisher ID: 3422

DOI: 10.1007/s00018-019-03422-9

PMC ID: 7058677

PubMed ID: 31893312

SO-VID: 4d1e9385-cb7c-4cb8-9f6f-35052ef64ecf

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 4 December 2019

Date revision received : 4 December 2019

Date accepted : 10 December 2019

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ScienceOpen disciplines: Molecular biology

Keywords: age-related macular degeneration,angiogenesis,hypoxia-inducible factors,gene therapy

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ScienceOpen disciplines: Molecular biology

Keywords: age-related macular degeneration, angiogenesis, hypoxia-inducible factors, gene therapy

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

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Karger: Ophthalmology

Most cited references 189

Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

Endothelial cell migration during angiogenesis.

Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

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