Cellular and molecular events in corneal wound healing: significance of lipid signalling

Bazán, Haydee E. P.

doi:10.1016/j.exer.2004.12.023

Cited by 65 publications

(52 citation statements)

References 70 publications

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“…The cornea and retina express abundant surface CD36 (18,19,23) and are rich in polyunsaturated phospholipids (32,56,57), which renders them particularly susceptible to oxidant stress. It was therefore intriguing to observe a substantial rise in CD36 corneal and retinal mRNA expression following hypoxia (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Up-regulates CD36 Expression and Function via Hypoxia-inducible Factor-1- and Phosphatidylinositol 3-Kinase-dependent Mechanisms

Mwaikambo

Yang

Chemtob

et al. 2009

Journal of Biological Chemistry

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Neovascular and degenerative diseases of the eye are leading causes of impaired vision and blindness in the world. Hypoxia or reduced oxygen tension is considered central to the pathogenesis of these disorders. Although the CD36 scavenger receptor features prominently in ocular homeostasis and pathology, little is known regarding its modulation by hypoxia. Herein we investigated the role and regulation of CD36 by hypoxia and by the major hypoxia effector, hypoxia-inducible factor (HIF)-1. In vivo, hypoxia markedly induced CD36 mRNA in corneal and retinal tissue. Subsequent experiments on human retinal pigment epithelial cells revealed that hypoxia time-dependently increased CD36 mRNA, protein, and surface expression; these responses were reliant upon reactive oxygen species production. As an important novel finding, we demonstrate that hypoxic stimulation of CD36 is mediated by HIF-1; HIF-1␣ down-regulation abolished CD36 induction by both hypoxia and cobalt chloride. Sequence analysis of the human CD36 promoter region revealed a functional HIF-1 binding site. A luciferase reporter construct containing this promoter fragment was activated by hypoxia, whereas mutation at the HIF-1 consensus site decreased promoter activation. Specific binding of HIF-1 to this putative site in hypoxic cells was detected by a chromatin immunoprecipitation assay. Interestingly, inhibition of the phosphatidylinositol 3-kinase pathway blocked the hypoxia-dependent induction of CD36 expression and promoter activity. Functional ramifications of CD36 hypoxic accumulation were evinced by CD36-dependent increases in scavenging and anti-angiogenic activities. Together, our findings indicate a novel mechanism by which hypoxia induces CD36 expression via activation of HIF-1 and the phosphatidylinositol 3-kinase pathway.Hypoxia, a reduction in cellular oxygen tension, is a key determinant of tissue pathology and survival during tumor development and ischemic diseases including retinopathies, myocardial infarction, and atherosclerosis. In response to hypoxia, mammalian cells express a variety of gene products important for erythropoiesis, angiogenesis, and glycolysis, thereby improving tissue oxygenation and facilitating metabolic demands (1, 2). These adaptive responses require the concerted activation of various transcription factors including hypoxia-inducible factor-1 (HIF-1), 4 which is generally considered the master regulator of oxygen homeostasis (2-5). HIF-1 is a heterodimer comprised of an oxygen-regulated ␣ subunit (HIF-1␣) and the ubiquitous aryl hydrocarbon receptor nuclear translocator (ARNT or HIF-1␤) (4, 6, 7). HIF-1␣ protein turnover in normoxia is very rapid due to the action of prolyl hydroxylases. These oxygen-dependent enzymes hydroxylate two conserved proline residues of HIF-1␣, promoting binding of the Von Hippel-Lindau protein, ubiquitination, and subsequent proteosomal degradation. Under hypoxic conditions the prolyl hydroxylases are inhibited, thereby allowing stabilization and accumulation of the HIF-1␣ protein (4 -6,...

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Section: Discussionmentioning

confidence: 99%

Hypoxia Up-regulates CD36 Expression and Function via Hypoxia-inducible Factor-1- and Phosphatidylinositol 3-Kinase-dependent Mechanisms

Mwaikambo

Yang

Chemtob

et al. 2009

Journal of Biological Chemistry

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“…Such an interaction is consistent with evidence provided for the existence of crosstalk in human corneal epithelial cells. 27 The effects of the broad-spectrum phosphatase inhibitor sodium orthovanadate (100 M), the MKP-1 inhibitor Ro 31-8220 (10 M), and the PP2A inhibitor okadaic acid (10 nM) on maximum EGF-induced increases in Erk1/2 and p38 phosphorylation status were also evaluated (Fig. 2).…”

Section: Pp-mediated Crosstalk Between Erk1/2 and P38 Pathwaysmentioning

confidence: 99%

Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells

Wang

Yang

Tachado

et al. 2006

Invest. Ophthalmol. Vis. Sci.

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“…As mentioned, human endothelial cells have a very low mitotic rate, and with aging cell loss occurs. Stress caused by contact lens wear and refractive and intraocular surgery can also alter endothelial density; therefore, epi-LxA4 could be important for protecting the integrity of the endothelium and could be useful in eye banking procedures for storing corneas for transplants after previous incubation with epi-LxA4 ( 80 ).…”

Section: Lipids In Corneal Pathologiesmentioning

confidence: 99%

Significance of lipid mediators in corneal injury and repair

Kenchegowda

Bazán

2010

Journal of Lipid Research

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ers of the cornea function in a synchronized way to ensure this transparency.Corneal tissue has three distinct layers, the epithelial, stroma, and endothelial layers, and two acellular regions, the Bowman's layer, which separates the epithelium from the stroma, and the Descemet's membrane, which is between the stroma and the endothelium ( Fig. 1A ). All three layers have a uniform and consistent arrangement throughout the tissue in order to precisely bend and transmit light, fi rst to the lens and then to the retina.The corneal epithelium is the most outer layer, consisting of fi ve to seven layers of stratifi ed nonkeratinized epithelia. The basal cells have a prominent nucleus, are mitotically active, and adhere to the basement membrane through an adhesion complex that anchors the epithelium to the Bowman's layer. Turnover of epithelial cells occurs every fi ve to seven days by displacement of existing cells, which begin their movement toward the surface to then form two to three layers of wing-shaped cells; the cells then begin terminal differentiation and desquamation. The outer-most layer of the epithelium is in intimate contact with the tear fi lm that keeps the surface moist and free of damage that can result from drying (dry eye). This is The cornea, known as the "window of the eye," has two major functions: to protect the intraocular structures and to refract light. In fact, the cornea accounts for two-thirds of the refractive power of the eye. The most important characteristic of this tissue is its transparency, and the lay-

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Cellular and molecular events in corneal wound healing: significance of lipid signalling

Cited by 65 publications

References 70 publications

Hypoxia Up-regulates CD36 Expression and Function via Hypoxia-inducible Factor-1- and Phosphatidylinositol 3-Kinase-dependent Mechanisms

Hypoxia Up-regulates CD36 Expression and Function via Hypoxia-inducible Factor-1- and Phosphatidylinositol 3-Kinase-dependent Mechanisms

Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells

Significance of lipid mediators in corneal injury and repair

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