Antisense Inhibition of Basic Fibroblast Growth Factor Induces Apoptosis in Vascular Smooth Muscle Cells

Fox, Jacob H.; Shanley, Jason

doi:10.1074/jbc.271.21.12578

Cited by 100 publications

(47 citation statements)

References 42 publications

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“…FGF-2 has also been implicated as a survival factor for a variety of quiescent or terminally differentiated cells (33). Smooth muscle cells in culture maintain differentiated characteristics via autocrine expression of FGF-2 and enter apoptosis when this secretion is blocked (34). Keratocytes express both mRNA for FGF-2 and for its receptor (35).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Promotes Keratan Sulfate Proteoglycan Expression by Keratocytes in Vitro

Long¹,

Roth²,

Tasheva³

et al. 2000

Journal of Biological Chemistry

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Keratocytes of the corneal stroma produce a specialized extracellular matrix responsible for corneal transparency. Corneal keratan sulfate proteoglycans (KSPG) are unique products of keratocytes that are down-regulated in corneal wounds and in vitro. This study used cultures of primary bovine keratocytes to define factors affecting KSPG expression in vitro. KSPG metabolically labeled with [35 S]sulfate decreased during the initial 2-4 days of culture in quiescent cultures with low serum concentrations (0.1%). Addition of fetal bovine serum, fibroblast growth factor-2 (FGF-2), transforming growth factor ␤, or platelet derived growth factor all stimulated cell division, but only FGF-2 stimulated KSPG secretion. Combined with serum, FGF-2 also prevented serum-induced KSPG down-regulation. KSPG secretion was lost during serial subculture with or without FGF-2. Expression of KSPG core proteins (lumican, mimecan, and keratocan) was stimulated by FGF-2, and steady state mRNA pools for these proteins, particularly keratocan, were significantly increased by FGF-2 treatment. KSPG expression therefore is supported by exogenous FGF-2 and eliminated by subculture of the cells in presence of serum. FGF-2 stimulates KSPG core protein expression primarily through an increase in mRNA pools.The corneal stroma is a disc of connective tissue that constitutes about 90% of the mammalian cornea. This tissue consists of a unique transparent extracellular matrix populated by keratocytes, flattened mesenchymal cells responsible for production and maintenance of this matrix. In healing corneal wounds keratocytes become activated, begin mitosis, and migrate to the wound location, where they secrete nontransparent scar components (1, 2). Cells in the healing wound are characterized by secretion of pro-inflammatory cytokines such as interleukin-1␣ and proteolytic enzymes involved in tissue remodeling, collagenase, gelatinase, and stromelysin (3, 4). This remodeling (fibroblastic) phenotype is simulated in vitro when keratocytes are cultured in medium containing fetal bovine serum and subcultured by trypsinization (5).The extracellular matrix of the normal corneal stroma is characterized by a unique class of molecules known as the corneal keratan sulfate proteoglycans (KSPG). 1 These consist of three structurally related proteins modified with N-linked keratan sulfate chains (6). The three proteins (lumican, keratocan, and mimecan) are found in a number of connective tissues but are expressed at much higher levels in the cornea compared with noncorneal tissues (7-9). In noncorneal tissues, these proteins are not modified with keratan sulfate (10). The high level of expression of these three proteins combined with a specialized glycosylation is a property unique to keratocytes and constitutes an essential feature of the role of the keratocyte in maintenance of corneal transparency. This conclusion is supported by the recent demonstration that mice bearing null mutations in the lumican gene lose corneal transparency, whereas mice with a similar...

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Promotes Keratan Sulfate Proteoglycan Expression by Keratocytes in Vitro

Long¹,

Roth²,

Tasheva³

et al. 2000

Journal of Biological Chemistry

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“…These growth factors partially prevent apoptosis of human or rat VSMCs cultured under low serum conditions (Bai et al, 1999;Bennett et al, 1995a;Fox & Shanley, 1996;Pollman et al, 1999a) in part by favouring the anti-apoptotic potential of the Bcl-2 family of proteins. For example, IGF-I stimulates increased expression of the inactive, phosphorylated form of Bad by a PI3-kinase-dependent pathway (Bai et al, 1999).…”

Section: Survival Pathwaysmentioning

confidence: 99%

Apoptosis in the vasculature: mechanisms and functional importance

Mallat¹,

Tedgui²

2000

British J Pharmacology

307

214

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Apoptotic death has now been recognized in a number of common and threatening vascular diseases, including atherosclerosis. Interest in apoptosis research relates to the fact that apoptosis, in contrast to oncosis, is a highly regulated process of cell death which raises the hope for the development of speci®c therapeutic strategies to alter disease progression. This review summarizes the mechanisms involved in vascular endothelial and smooth muscle cell survival/apoptosis, and the potential roles of apoptotic death in atherosclerosis and restenosis. The potential e ects of modulation of apoptosis in these diseases are also discussed.

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“…For instance, bFGF can increase survival of neurons (Blottner and Baumgarten, 1992;Zawada et al, 1996), quiescent ®broblasts (Tamm et al, 1991) and cAMP-stimulated rat ovarian granulosa cells (Aharoni et al, 1995). Antisense inhibition of bFGF expression induces apoptosis in vascular smooth muscle cells (Fox and Shanley, 1996). Furthermore, bFGF can protect endothelial cells against radiationinduced apoptosis in vivo and in vitro (Fuks et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Induction of Mdm2 and enhancement of cell survival by bFGF

et al. 1997

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Basic ®broblast growth factor (bFGF) can exert mitogenic and viability-promoting e ects in a wide range of biological systems. The biochemical activities mediating the cell survival function of bFGF are largely unknown. We report here that exposure of ®broblasts to bFGF, which confers upon them increased survival, also causes at the same time an increase in cellular levels of the Mdm2 oncoprotein. Cells constitutively exposed to a bFGF autocrine loop are more refractory to killing by cisplatin. This increased chemoresistance coincides with elevated Mdm2 and reduced activation of the endogenous p53, resulting in ine cient transcriptional activation of the bax gene promoter. Importantly, unlike Mdm2 accumulation in ®broblasts exposed to DNA damage, induction of Mdm2 by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA damageinduced apoptosis and the ability of Mdm2 to block p53-mediated cell death are well established. These ®ndings therefore suggest that induction of Mdm2 and the subsequent inhibition of p53 function may contribute, at least partially, to the anti-apoptotic e ects of bFGF and possibly some other survival factors.

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Antisense Inhibition of Basic Fibroblast Growth Factor Induces Apoptosis in Vascular Smooth Muscle Cells

Cited by 100 publications

References 42 publications

Fibroblast Growth Factor-2 Promotes Keratan Sulfate Proteoglycan Expression by Keratocytes in Vitro

Fibroblast Growth Factor-2 Promotes Keratan Sulfate Proteoglycan Expression by Keratocytes in Vitro

Apoptosis in the vasculature: mechanisms and functional importance

Induction of Mdm2 and enhancement of cell survival by bFGF

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