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AlphaB-crystallin regulation of angiogenesis by modulation of VEGF.

ABSTRACT: alphaB-crystallin is a chaperone belonging to the small heat shock protein family. Herein we show attenuation of intraocular angiogenesis in alphaB-crystallin knockout (alphaB-crystallin(-/-)) mice in 2 models of intraocular disease: oxygen-induced retinopathy and laser-induced choroidal neovascularization. Vascular endothelial growth factor A (VEGF-A) mRNA and hypoxia inducible factor-1alpha protein expression were induced during retinal angiogenesis, but VEGF-A protein expression remained low in alphaB-crystallin(-/-) retina versus wild-type mice, whereas VEGF-R2 expression was not affected. Both alphaB-crystallin and its phosphorylated serine59 formwere expressed, and immunoprecipitation revealed alphaB-crystallin binding to VEGF-A but not transforming growth factor-beta in cultured retinal pigment epithelial (RPE) cells. alphaB-crystallin and VEGF-A are colocalized in the endoplasmic reticulum in RPE cells under chemical hypoxia. alphaB-crystallin(-/-) RPE showed low VEGF-A secretion under serum-starved conditions compared with wild-type cells. VEGF-A is polyubiquitinated in control and alphaB-crystallin siRNA treated RPE; however, mono-tetra ubiquitinated VEGF-A increases with alphaB-crystallin knockdown. Endothelial cell apoptosis in newly formed vessels was greater in alphaB-crystallin(-/-) than wild-type mice. Proteasomal inhibition in alphaB-crystallin(-/-) mice partially restores VEGF-A secretion and angiogenic phenotype in choroidal neovascularization. Our studies indicate an important role for alphaB-crystallin as a chaperone for VEGF-A in angiogenesis and its potential as a therapeutic target.

SUBMITTER: Kase S

PROVIDER: S-EPMC2858494 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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alphaB-crystallin regulation of angiogenesis by modulation of VEGF.

Kase Satoru S He Shikun S Sonoda Shozo S Kitamura Mizuki M Spee Christine C Wawrousek Eric E Ryan Stephen J SJ Kannan Ram R Hinton David R DR

Blood 20091218 16

alphaB-crystallin is a chaperone belonging to the small heat shock protein family. Herein we show attenuation of intraocular angiogenesis in alphaB-crystallin knockout (alphaB-crystallin(-/-)) mice in 2 models of intraocular disease: oxygen-induced retinopathy and laser-induced choroidal neovascularization. Vascular endothelial growth factor A (VEGF-A) mRNA and hypoxia inducible factor-1alpha protein expression were induced during retinal angiogenesis, but VEGF-A protein expression remained low ...[more]

PMID: 20023214

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Project description:We previously reported that zebrafish alphaB-crystallin is not constitutively expressed in nervous or muscular tissue and has reduced chaperone-like activity compared with its human ortholog. Here we characterize the tissue expression pattern and chaperone-like activity of a second zebrafish alphaB-crystallin. Expressed sequence tag analysis of adult zebrafish lens revealed the presence of a novel alpha-crystallin transcript designated cryab2 and the resulting protein alphaB2-crystallin. The deduced protein sequence was 58.2% and 50.3% identical with human alphaB-crystallin and zebrafish alphaB1-crystallin, respectively. RT-PCR showed that alphaB2-crystallin is expressed predominantly in lens but, reminiscent of mammalian alphaB-crystallin, also has lower constitutive expression in heart, brain, skeletal muscle and liver. The chaperone-like activity of purified recombinant alphaB2 protein was assayed by measuring its ability to prevent the chemically induced aggregation of alpha-lactalbumin and lysozyme. At 25 degrees C and 30 degrees C, zebrafish alphaB2 showed greater chaperone-like activity than human alphaB-crystallin, and at 35 degrees C and 40 degrees C, the human protein provided greater protection against aggregation. 2D gel electrophoresis indicated that alphaB2-crystallin makes up approximately 0.16% of total zebrafish lens protein. Zebrafish is the first species known to express two different alphaB-crystallins. Differences in primary structure, expression and chaperone-like activity suggest that the two zebrafish alphaB-crystallins perform divergent physiological roles. After gene duplication, zebrafish alphaB2 maintained the widespread protective role also found in mammalian alphaB-crystallin, while zebrafish alphaB1 adopted a more restricted, nonchaperone role in the lens. Gene duplication may have allowed these functions to separate, providing a unique model for studying structure-function relationships and the regulation of tissue-specific expression patterns.

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AlphaB-crystallin regulation of angiogenesis by modulation of VEGF.

Publications

alphaB-crystallin regulation of angiogenesis by modulation of VEGF.

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