Hypoxia inducible factor (HIF-1 alpha) is known to ��-Nicotinamide participate in atherosclerosis and to stimulate apoptosis signal-regulating kinase 1 (ASK-1), one of the mitogen-activated protein kinases, which is activated by various extracellular stimuli and involved in a variety of cellular function.
Methods: We tested carotid artery specimens from 50 subjects who underwent angioplasty and five age-matched controls for either Western blot or histologic analysis. The hypoxic status was investigated by means of HIF-1 alpha expression in carotid specimens.
Results: HIF-1 alpha was significantly upregulated in carotid specimens with respect to controls (P < .05), ASK-1 was detected in plaques
of any composition from lipidic to
calcific, and this expression increased with the stage of the plaque and with the expression of inflammatory (p-ERK, RANK-L, OPG) and apoptotic molecules (caspase 9, p-p-38, and p-JNK).
Conclusion: Our data suggest that hypoxia is the key regulating factor that triggers inflammation as well as apoptosis in the human atherosclerotic plaque. (J Vasc Surg 2010;52:1015-21.)”
“The sigma receptor 1 (sigma R1) has been shown to modulate the activity of several voltage- and ligand-gated channels. Using patch-clamp techniques in rat retinal slice preparations, we demonstrated that activation of sigma R1 by SHP099 concentration SKF10047 (SKF) or PRE-084 suppressed N-methyl-D-aspartate (NMDA) receptor-mediated current responses from both ON and OFF type ganglion cells (GCs), dose-dependently, and the effect could be blocked by the sigma R1 antagonist BD1047 or the sigma R antagonist haloperidol. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-beta-S or the G(i/o) activator mastoparan. We further explored the intracellular signaling pathway responsible for the SKF-induced suppression of NMDA responses. Application of either Ganetespib molecular weight cAMP/the PKA inhibitor Rp-cAMP or cGMP/the PKG inhibitor KT5823 did not change the SKF-induced
effect, suggesting the involvement of neither cAMP/PKA nor cGMP/PKG pathway. In contrast, suppression of NMDA responses by SKF was abolished by internal infusion of the phosphatidylinostiol-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine-PLC inhibitor D609. SKF-induced suppression of NMDA responses was dependent on intracellular Ca(2+) concentration ([Ca(2+)](i)), as evidenced by the fact that the effect was abolished when [Ca(2+)](i) was buffered with 10 mM BAPTA. The SKF effect was blocked by xestospongin-C/heparin, IP(3) receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of protein kinase C inhibitors Bis IV and Go6976 eliminated the SKF effect.