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Heme Oxygenase-1 Mediates Up-Regulation of Adhesion Molecule Expression Induced by Peroxynitrite in Endothelial Cells

Yanping Zhang, MD

Yang Gu, MD

David F. Lewis, MD

Departments of Obstetrics and Gynecology, and Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana

Yuping Wang, MD, PhD

Departments of Obstetrics and Gynecology, and Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; ywang1{at}lsuhsc.edu

Objective: Endothelial cell (EC) activation with up-regulation of cellular adhesion molecule (CAM) expression is a pathophysiologic feature in preeclampsia (PE). Enhanced peroxynitrite formation in the vasculature of women with PE was also reported. This study was to test whether EC oxidative stress induced by peroxynitrite could up-regulate EC CAM expression, and whether heme oxygenase-1 (HO-1) has protective effects on this peroxynitrite-induced cellular response.

Methods: Confluent ECs were stimulated with 3-morpholinosydnonimine-HCl (SIN-1, a peroxynitrite generator) alone or combined with Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP, a peroxynitrite scavenger) up to 4 hours. EC surface protein expressions for ICAM, VCAM, P-selectin, and E-selectin were measured by colorimetric assay. ECs were also treated with Sn(IV) mesophorphyrin IX dichloride (SnMP, a HO-1 inhibitor) to determine if HO-1 was involved in the increased CAM expression in stressed cells. Protein and mRNA expressions for HO-1 were determined by Western blot analysis and reverse-transcriptase polymerase chain reaction (RT-PCR). Data are presented as the mean ± SE and analyzed by analysis of variance (ANOVA).

Results: Endothelial CAM expressions for VCAM, P-selectin, and E-selectin, but not ICAM, were significantly increased in SIN-1-treated ECs. Protein and mRNA expressions for HO-1 were also up-regulated in cells treated with SIN-1. MnTMPyP blocked both mRNA and protein expressions for HO-1, whereas SnMP only blocked HO-1 protein expression. Both MnTMPyP and SnMP abolished SIN-1-induced up-regulation of VCAM, P-selectin, and E-selectin expression in ECs.

Conclusions: Peroxynitrite-induced EC oxidative stress produces differential effects on CAM expression, which may be mediated by HO-1 regulation. Our results suggest that increased peroxynitrite formation in the maternal vasculature may contribute to the increased CAM expression and enhanced neutrophil-endothelial interaction associated with PE.

Key Words: Endothelial cells • adhesion molecule • HO-1 • peroxynitrite • preeclampsia

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