Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Rossmann, C.
HOCl-HDL-mediated Induction of HO-1 in human Endothelial Cells
[ Dissertation ] Medical University of Graz, 2011. pp. 105
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Rossmann Christine Renate
- Betreuer*innen:
- Malle Ernst
- Altmetrics:
- Abstract:
- The phagocytic enzyme myeloperoxidase (MPO) is the prime enzyme that generates hypochlorous acid (HOCl) from H2O2 in the presence of physiological chloride concentrations. Modification of the anti-atherogenic high-density lipoprotein (HDL) by HOCl, added as reagent or generated enzymatically by the MPO-H2O2-chloride-system, generates a pro-atherogenic lipoprotein particle. HOCl-HDL exhibits an impaired capacity during "reverse cholesterol transport" and represents a high uptake form for macrophages. MPO colocalizes with HOCl-modified HDL/apolipoprotein A-I in human atherosclerotic lesions and on endothelial cells lining the blood vessel. Furthermore, HOCl-HDL impairs expression and activity of vasculoprotective endothelial nitric oxide synthase (eNOS). The induction of heme oxygenase-1 (HO-1) and its products is considered a protection mechanism in endothelial cells in response to oxidative stress and endothelial dysfunction. The present study aimed at identifying the underlying pathways of HO-1 induction by HOCl-HDL in human endothelial EA.hy926 cells Our observations revealed that HDL modified by HOCl added as reagent or generated enzymatically, induced (i) phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPKs), (ii) expression of transcription factor early-growth response-1 (Egr-1), and (iii) HO-1. Furthermore, HOCl-HDL treatment induced nuclear translocation of Egr-1 and enhanced Egr-1 DNA-binding activity. Inhibition of p42/44 MAPK decreased HOCl-HDL-mediated expression and nuclear translocation of Egr-1 as well as expression of HO-1. Knockdown of Egr-1 via RNA interference resulted in a decrease in Egr-1 nuclear translocation and a reduction of HO-1 on mRNA and protein level in response to HOCl-HDL. Moreover, inhibition of phosphatidyl-inositol-3-kinase decreased HOCl-HDL-induced HO-1 expression on protein level. Although HOCl-HDL caused a decrease in eNOS mRNA level, no reduction in HOCl-HDL-mediated eNOS protein expression or eNOS activity was observed. Furthermore, HOCl-HDL treatment did not cause any anti-proliferative effects, nor induced apoptosis in human endothelial cells. The present study demonstrates that HO-1 is induced in response to HOCl-HDL via activation of p42/44 MAPK and transcription factor Egr-1 or alternatively via activation of phosphatidyl-inositol-3-kinase, thus proposing two novel rescue mechanisms in endothelial cells.