Coronin 1A depletion protects endothelial cells from TNFα-induced apoptosis by modulating p38β expression and activation

초록

Coronins are conserved actin-binding proteins that regulate various cellular processes such as migration and endocytosis. Among coronin family members, coronin 1A is highly expressed in hematopoietic lineage cells where it regulates cell homeostasis. However, the expression and function of coronin 1A in endothelial cells have not yet been elucidated. We found that coronin 1A is expressed in the human umbilical vein endothelial cell (HUVEC) and human brain microvascular endothelial cell (HBMVEC). In HUVEC depleted of coronin 1A by siRNA transfection, tumor necrosis factor alpha (TNF alpha) + cyclohexamide (CHX) treatment resulted in a decrease in the number of terminal deoxyrtucleotidyl transferase dUTP nick end labeling (TUNEL) positive apoptotic cells. Coronin 1A depletion also resulted in the suppression of caspase 3 and poly(ADP-ribose) polymerase cleavage and a reduction in caspase 3 activity. Next, we examined TNF alpha-induced activation of several pro- and anti-apoptotic signaling molecules to find the target molecule of coronin 1A and found that p38 phosphorylation was enhanced by TNFa stimulation in coronin 1A-depleted HUVEC. Among the p38 isoforms, the expression of p38 beta was significantly upregulated after coronin 1A depletion, suggesting that the expression and phosphorylation of antiapoptotic p38 beta were significantly induced in coronin 1A-depleted HUVEC. Inhibition of p38 13 upregulation in coronin 1A-depleted HUVEC restored the cleavage of caspase 8 and caspase 3 and induced more apoptosis than in coronin 1A-depleted HUVEC in response to TNF alpha + CHX. These findings suggest that coronin 1A modulates endothelial cell apoptosis by regulating p38 beta expression and activation. (C) 2015 Elsevier Inc. All rights reserved.

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