Dysregulated expression of ACTN4 contributes to endothelial cell injury via the activation of the p38-MAPK/p53 apoptosis pathway in preeclampsia.
Preeclampsia (PE) is a hypertensive disease associated with increased endothelial cell dysfunction caused by systemic oxidative stress. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that are upregulated in several types of cancer. However, its role in PE remains unclear. In this study, we found that ACTN4 was localized in placenta vascular endothelial cells (ECs), and its expression was downregulated in primary human umbilical vein endothelial cells (HUVECs) from severe preeclamptic patients compared to that in HUVECs from normotensive pregnant women. ACTN4 expression was also decreased in normotensive HUVECs treated with H2O2. Downregulation of ACTN4 by siRNA or H2O2 treatment promoted normotensive HUVEC apoptosis and increased p38-MAPK phosphorylation along with elevated levels of p53 phosphorylation, caspase cascade proteins, and bax and repressed expression of bcl-2. Conversely, upregulation of ACTN4 in PE HUVECs significantly inhibited apoptosis and decreased p38-MAPK phosphorylation compared to that of the PE HUVEC controls. In addition, overexpression of ACTN4 in normotensive HUVECs attenuated H2O2 treatment-induced apoptosis with decreased p53 phosphorylation, caspase cascade, and bax expression levels and increased expression of bcl-2 compared to that of only H2O2 treatment. Moreover, the suppression of ACTN4 induced apoptosis, which could be blocked by the p38-MAPK inhibitor SB202190. Collectively, these results demonstrate that dysregulated ACTN4 expression may be associated with PE due to its effects on endothelial cell apoptosis via the p38-MAPK/p53 apoptosis pathway.
['Zhao|Jianlin|J|', 'Peng|Wei|W|', 'Ran|Yuxin|Y|', 'Ge|Huisheng|H|', 'Zhang|Chen|C|', 'Zou|Hong|H|', 'Ding|Yubin|Y|', 'Qi|Hongbo|H|']
D000185:Actinin D000328:Adult D017209:Apoptosis D020169:Caspases D005260:Female D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D006861:Hydrogen Peroxide D018384:Oxidative Stress D011225:Pre-Eclampsia D011247:Pregnancy D017382:Reactive Oxygen Species D016159:Tumor Suppressor Protein p53 D055815:Young Adult D048051:p38 Mitogen-Activated Protein Kinases
Apoptosis Preeclampsia Endothelial cell dysfunction Oxidative stress P38-MAPK/p53 pathway