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and Activation of Caspase-3 in Hypoxia-Reoxygenated Bone Marrow Stroma Is Negatively Regulated by the Delayed Production of Substance P1
Departments of
*
Medicine and
Surgery, Trauma Division, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
The bone marrow (BM), which is the major site of immune cell
development in the adult, responds to different stimuli such as
inflammation and hemorrhagic shock. Substance P (SP) is the major
peptide encoded by the immune/hemopoietic modulator gene,
preprotachykinin-1 (PPT-I). Differential gene expression
using a microarray showed that SP reduced hypoxia-inducible factor-1
(HIF-1) mRNA levels in BM stroma. Because long-term hypoxia induced
the expression of PPT-I in BM mononuclear cells, we used timeline
studies to determine whether PPT-I is central to the
biologic responses of BM stroma subjected to 30-min hypoxia
(pO2 = 35 mm Hg) followed by reoxygenation. HIF-1
mRNA and protein levels were increased up to 12 h. At this time,
-PPT-I mRNA was detected with the release of SP at 16 h. SP
release correlated with down-regulation of HIF-1 to baseline. A
direct role for SP in HIF-1 expression was demonstrated as follows:
1) transient knockout of -PPT-I showed an increase in HIF-1
expression up to 48 h of reoxygenation; and 2) HIF-1 expression
remained baseline during reoxygenation when stroma was subjected to
hypoxia in the presence of SP. Reoxygenation activated the PPT-I
promoter with concomitant nuclear translocation of HIF-1 that can
bind to the respective consensus sequences within the PPT-I promoter.
SP reversed active caspase-3, an indicator of apoptosis and
erythropoiesis, to homeostasis level after reoxygenation of hypoxic
stroma. The results show that during reoxgenation the
PPT-I gene acts as a negative regulator on the
expression of HIF-1 and active caspase-3 in BM stroma
subjected to reoxygenation.
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