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Farm Przegl Nauk, 2009,2
DISCUSSION
Oxidative stress is known to affect tissue metabolism
[38,39]. It participates in pathogenesis of inflammation
[40,41] and diabetes [41,42], promotes carcinogenesis [1]
and induces cellular senescence resulting from accumulation
of oxidative damage in DNA, lipids and proteins [43].
Collagen, which accounts for about one third of total body
proteins is essential not only for the maintenance of the connective
tissue, but also for interaction with integrins. Activation
of these receptors by extracellular matrix proteins, e.g.
collagen, regulates cellular gene expression, differentiation,
cell growth [44] and plays an important role in wound repair
[45], tumorigenicity and invasiveness [46].
This study suggests, that oxidative stress exerts inhibitory
effect on collagen biosynthesis in human dermal fibroblasts.
Similar effect on collagen production was previously
demonstrated in human cardiac fibroblasts exposed to varying
concentrations of hydrogen peroxide or xanthine plus
xanthine oxide [7]. In order to explain the mechanism of this
process, we considered prolidase as a target enzyme.
Prolidase activity has been demonstrated to play an important
role in regulation of collagen biosynthesis in fibroblasts
[10-12]. In fact, the enzyme expression was decreased
in fibroblasts exposed to t-BHP. Decreased prolidase expression
in these cells was accompanied by a decrease in the expression
of phosphorylated FAK protein. The correlation is
well known phenomenon. Activation of β 1 -integrin receptor
that is known to increase in prolidase expression and activity
[16, 36] leads to phosphorylation of FAK [17]. Therefore
decrease in expression of FAK in t-BHP treated fibroblasts
may explain decrease in prolidase expression. Similarly decreased
expression of MAP- kinases (ERK 1 and ERK 2 ) was
observed in t-BHP treated cells.
Extracellular signal-regulated kinases pathway constitutes
a major one, through which growth factor receptors
transmit signals to the nucleus. It is known, that some growth
factor receptors (EGFR, PDGFR or T-cell receptor) undergo
phosphorylation in response to treatment with oxidants.
Their phosphorylation leads to activation of p44/42 MAPK
signaling pathway [47-52]. However, it has been recently
shown, that oxidative stress can variously modulate ERKs
activity in a time- and dose-dependent manner [53,54]. In
addition, reactive carbonyl compounds, glyoxal and methylglyoxal
formed extensively in conditions of oxidative stress
have been demonstrated to be capable of dephosphorylation
of intracellular phospho-ERKs, what results in their inactivation
[55].
IGF-I receptor is a receptor-tyrosine kinase that plays a
critical role in signaling that leads to cell survival and proliferation.
It is also a strong stimulator of collagen and DNA
biosynthesis [21, 26]. It has been proposed, that activation
of this receptor may protect different cells from oxidative
stress [56-58] and regulate their resistance to the action of
oxidants [59].
We found that down-regulation of IGF-I receptor expression
in fibroblasts submitted to oxidative stress was accompanied
by parallel changes in expression of both MAP-kinases
(ERK 1 and ERK 2 ). Simultaneously, DNA biosynthesis
in fibroblasts treated with t-BHP decreased during the time
32
course of the experiment. In view of these data it seems that
decrease in collagen biosynthesis and cell division caused
by oxidative stress may be mostly a consequence of disturbances
in β 1 -integrin and IGF-I receptor signaling.
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