The Anti-Apoptotic Properties of APEX1 in the Endothelium Require the First 20 Amino Acids and Converge on Thioredoxin-1.
The APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1) has a disordered N-terminus, a redox, and a DNA repair domain. APEX1 has anti-apoptotic properties, which have been linked to both domains depending on cell type and experimental conditions.



As protection against apoptosis is a hallmark of vessel integrity, we wanted to elucidate whether APEX1 acts anti-apoptotic in primary human endothelial cells and, if so, what the underlying mechanisms are.



APEX1 inhibits apoptosis in endothelial cells by reducing Cathepsin D (CatD) cleavage, potentially by binding to the unprocessed form. Diminished CatD activation results in increased Thioredoxin-1 protein levels leading to reduced Caspase 3 activation. Consequently, apoptosis rates are decreased. This depends on the first twenty amino acids in APEX1, because APEX1 (21-318) induces CatD activity, decreases Thioredoxin-1 protein levels, and, thus, increases Caspase 3 activity and apoptosis. Along the same lines, APEX1 (1-20) inhibits Caspase 3 cleavage and apoptosis. Furthermore, re-expression of Thioredoxin-1 via lentiviral transduction rescues endothelial cells from APEX1 (21-318)-induced apoptosis. In an in vivo model of restenosis, which is characterized by oxidative stress, endothelial activation, and smooth muscle cell proliferation, Thioredoxin-1 protein levels are reduced in the endothelium of the carotids.



APEX1 acts anti-apoptotic in endothelial cells. This anti-apoptotic effect depends on the first 20 amino acids of APEX1.



As proper function of the endothelium during life span is a hallmark for individual health span, a detailed characterization of the functions of the APEX1N-terminus is required to understand all its cellular properties. Antioxid. Redox Signal. 26, 616-629.
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Nadine
N
Dyballa-Rukes
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Philipp
P
Jakobs
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Anna
A
Eckers
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Niloofar
N
Ale-Agha
2 Department of Pharmacology, University of Virginia , Charlottesville, Virginia.
Vlad
V
Serbulea
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Karin
K
Aufenvenne
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Tim-Christian
TC
Zschauer
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Lothar L
LL
Rabanter
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Sascha
S
Jakob
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Florian
F
von Ameln
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Olaf
O
Eckermann
2 Department of Pharmacology, University of Virginia , Charlottesville, Virginia.|3 Cardiovascular Research Center, University of Virginia , Charlottesville, Virginia.
Norbert
N
Leitinger
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Christine
C
Goy
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .
Joachim
J
Altschmied
1 IUF-Leibniz Research Institute for Environmental Medicine , Duesseldorf, Germany .|4 Medical Faculty, Central Institute of Clinical Chemistry and Laboratory Medicine, University of Duesseldorf , Duesseldorf, Germany .
Judith
J
Haendeler
D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006083:Graft Occlusion, Vascular / Q000235:genetics* / Q000473:pathology; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D013879:Thioredoxins / Q000096:biosynthesis* / Q000235:genetics
D000596:Amino Acids; D013879:Thioredoxins; D053148:Caspase 3; D002402:Cathepsin D; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
APEX1; N-terminus; Trx-1; anti-apoptotic