Interactive Expressions of HtrA1 and VEGF in Human Vitreous Humors and Fetal RPE Cells

Ng, Tsz Kin; Yam, Gary Hin Fai; Chen, Wei Qi; Lee, Vincent Y. W.; Chen, Haoyu; Chen, Li Jia; Choy, Kwong Wai; Yang, Zhenglin; Pang, Chi Pui

doi:10.1167/iovs.10-6773

Cited by 18 publications

(19 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our result is consistent with a recent study showing that the vitreous level of HtrA1 was significantly associated with that of VEGF in patients with eye diseases (ocular vascular diseases, retinal detachment, idiopathic macular hole, and traumatic injury) (47). Both HTRA1 and VEGF were up-regulated in human fetal RPE cells under stress conditions (47). In HTRA1 mice, VEGF may be up-regulated in response to the RPE stress induced by HTRA1 overexpression.…”

Section: Discussionsupporting

confidence: 93%

Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice

Jones

Kumar

Zhang

et al. 2011

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

Self Cite

135

139

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. Wet AMD includes typical choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV). The etiology and pathogenesis of CNV and PCV are not well understood. Genome-wide association studies have linked a multifunctional serine protease, HTRA1, to AMD. However, the precise role of HTRA1 in AMD remains elusive. By transgenically expressing human HTRA1 in mouse retinal pigment epithelium, we showed that increased HTRA1 induced cardinal features of PCV, including branching networks of choroidal vessels, polypoidal lesions, severe degeneration of the elastic laminae, and tunica media of choroidal vessels. In addition, HTRA1 mice displayed retinal pigment epithelium atrophy and photoreceptor degeneration. Senescent HTRA1 mice developed occult CNV, which likely resulted from the degradation of the elastic lamina of Bruch's membrane and up-regulation of VEGF. Our results indicate that increased HTRA1 is sufficient to cause PCV and is a significant risk factor for CNV.A dvanced age-related macular degeneration (AMD) can be classified into wet AMD and geographic atrophy (1, 2). Wet AMD includes the typical choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV). CNV is caused by the growth of new blood vessels from the choroid into the subretinal pigment epithelium (RPE) and subretinal spaces, whereas PCV is caused by inner choroidal vessel abnormalities (3). PCV has two key features on indocyanine green angiography (ICGA): polypoidal vascular dilations and a network of branching abnormal choroid vessels (4). Both CNV and PCV can lead to recurrent serous exudation and hemorrhages (5). The etiology and pathogenesis of CNV and PCV are largely unknown.Numerous genetic association studies have shown that chromosome 10q26 is a major candidate region associated with the susceptibility of several types of AMD (6, 7), including PCV (8-10). The linkage peak was refined to two neighboring genes, HTRA1 (11, 12) and ARMS2 (or LOC387715) (13). HTRA1 is a multifunctional serine protease that is ubiquitously expressed in mammalian tissues (14, 15) but ARMS2 is primate-specific, with a proposed function in mitochondria (13, 16), extracellular matrix (17), or as a noncoding RNA (18). Variants in this region are in strong linkage disequilibrium (11-13, 16). There are three major competing hypotheses attributing increased risk of AMD to (i) increased HTRA1 (11, 12), (ii) decreased ARMS2 (16), or (iii) both increased HTRA1 and decreased ARMS2 (19). However, a series of studies on the influence of AMD-associated polymorphisms on the expression of ARMS2 and HTRA1 have yielded widely conflicting results (12,16,(18)(19)(20)(21)(22)(23)(24). As a result, the functional involvement of either HTRA1 or ARMS2 in AMD remains uncertain, despite strong genetic evidence (18,22). To clarify the role of HTRA1 in AMD pathogenesis, we transgenically expressed human HTRA1 in mouse RPE. We showed that increased HTRA1 is ...

show abstract

Section: Discussionsupporting

confidence: 93%

Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice

Jones

Kumar

Zhang

et al. 2011

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

Self Cite

135

139

View full text Add to dashboard Cite

show abstract

“…We previously identified multiple genetic variants, such as CFH , HTRA1 and FPR1 genes6789, associated with AMD, and they could interact additively with oxidative stress-related condition, including cigarette smoking. Moreover, we also identified that HTRA1 expression is related to acute stress10, confirming that oxidative stress is an important player in AMD development.…”

supporting

confidence: 66%

“…We previously showed that the endoplasmic reticulum (ER) stress is related to RPE cell degeneration10. We therefore determined the expression of ER stress markers, such as activating transcription factor 6 (ATF6/ ATF6 ), 78 kDa glucose-regulated protein (GRP78/ HSPA5 ) and pancreatic ER kinase (PERK/ EIF2AK3 ), in ARPE-19 cells after sodium iodate treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Human RPE cell line (ARPE-19; CRL-2302) from American Type Culture Collection (Manassas, VA) has been established previously1041. They were maintained and expanded in Dulbecco’s modified Eagle’s medium and F-12 nutrient mixture (DF-12 culture medium; Gibco BRL, Rockville, MD) supplemented with 10% heat-inactivated fetal bovine serum (Gibco BRL) and 1x penicillin/streptomycin (Gibco BRL) at 37 °C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

Zhang

Brelén

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Age-related macular degeneration (AMD), characterized by progressive degeneration of retinal pigment epithelium (RPE), is the major cause of irreversible blindness and visual impairment in elderly population. We previously established a RPE degeneration model using an acute high dose sodium iodate to induce oxidative stress. Here we report findings on a prolonged treatment of low doses of sodium iodate on human RPE cells (ARPE-19). RPE cells were treated continuously with low doses (2–10 mM) of sodium iodate for 5 days. Low doses (2–5 mM) of sodium iodate did not reduce RPE cell viability, which is contrasting to cell apoptosis in 10 mM treatment. These low doses are sufficient to retard RPE cell migration and reduced expression of cell junction protein ZO-1. Phagocytotic activity of RPE cells was attenuated by sodium iodate dose-dependently. Sodium iodate also increased expression of FGF-2, but suppressed expression of IL-8, PDGF, TIMP-2 and VEGF. Furthermore, HTRA1 and epithelial-to-mesenchymal transition marker proteins were downregulated, whereas PERK and LC3B-II proteins were upregulated after sodium iodate treatment. These results suggested that prolonged exposure to non-lethal doses of oxidative stress induces RPE cell dysfunctions that resemble conditions in AMD. This model can be used for future drug/treatment investigation on AMD.

show abstract

“…Many of these studies suggest a link between HTRA1, fibronectin and stabilization of the extracellular matrix in AMD pathogenesis [8], [16], [17]. As an important signal protein promoting angiogenesis, VEGF should also be studied to determine if there is any connection with HTRA1 in AMD [18], [19]. Thus, we speculated that the expression of HTRA1 could be associated with fibronectin and VEGF and that it could ultimately be involved in the regulation of PCV.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HTRA1 Leads to Down-Regulation of Fibronectin and Functional Changes in RF/6A Cells and HUVECs

Jiang

Huang²,

Yu³

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

Multiple genetic studies have suggested that high-temperature requirement serine protease (HTRA1) is associated with polypoidal choroidal vasculopathy (PCV). To date, no functional studies have investigated the biological effect of HTRA1 on vascular endothelial cells, essential vascular components involved in polypoidal vascular abnormalities and arteriosclerosis-like changes. In vitro studies were performed to investigate the effect of HTRA1 on the regulation of fibronectin, laminin, vascular endothelial growth factor (VEGF), platelet derived growth factor receptor (PDGFR) and matrix metalloparoteinases 2 (MMP-2) and the role of HTRA1 in choroid-retina endothelial (RF/6A) and human umbilical vein endothelial (HUVEC) cells. Lentivirus-mediated overexpression of HTRA1 was used to explore effects of the protease on RF/6A and HUVEC cells in vitro. HTRA1 overexpression inhibited the proliferation, cell cycle, migration and tube formation of RF/6A and HUVEC cells, effects that might contribute to the early stage of PCV pathological lesions. Fibronectin mRNA and protein levels were significantly down-regulated following the upregulation of HTRA1, whereas the expressions of laminin, VEGF and MMP-2 were unaffected by alterations in HTRA1 expression. The decreased biological function of vascular endothelial cells and the degradation of extracellular matrix proteins, such as fibronectin, may be involved in a contributory role for HTRA1 in PCV pathogenesis.

show abstract

Interactive Expressions of HtrA1 and VEGF in Human Vitreous Humors and Fetal RPE Cells

Abstract: This study revealed an association between HtrA1 and VEGF in human vitreous humors and RPE cells. They are both related to stress and inflammatory conditions.

Cited by 18 publications

References 51 publications

Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice

Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice

Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

Overexpression of HTRA1 Leads to Down-Regulation of Fibronectin and Functional Changes in RF/6A Cells and HUVECs

Contact Info

Product

Resources

About