Stimulation of Wnt/β-catenin signaling pathway with Wnt agonist reduces organ injury after hemorrhagic shock.
BACKGROUND
Hemorrhagic shock is a leading cause of morbidity and mortality in surgery and trauma patients. Despite a large number of preclinical trials conducted to develop therapeutic strategies against hemorrhagic shock, there is still an unmet need for effective therapy for hemorrhage patients. Wnt/β-catenin signaling controls developmental processes and cellular regeneration owing to its central role in cell survival and proliferation. We therefore hypothesized that the activation of Wnt signaling reduces systemic injury caused by hemorrhagic shock.


METHODS
Adult male Sprague-Dawley rats underwent hemorrhagic shock by controlled bleeding of the femoral artery to maintain a mean arterial pressure of 30 mm Hg for 90 minutes, followed by resuscitation with crystalloid equal to two times the shed blood volume. After resuscitation, animals were infused with Wnt agonist (5 mg/kg) or vehicle (20% dimethyl sulfoxide in saline). Blood and tissue samples were collected 6 hours after resuscitation for analysis.


RESULTS
Hemorrhagic shock increased serum levels of aspartate aminotransferase, lactate, and lactate dehydrogenase. Treatment with Wnt agonist significantly reduced these levels by 40%, 36%, and 77%, respectively. Wnt agonist also decreased blood urea nitrogen and creatinine by 34% and 56%, respectively. The treatment reduced lung myeloperoxidase activity and interleukin 6 messenger RNA by 55% and 68%, respectively, and significantly improved lung histology. Wnt agonist treatment increased Bcl-2 protein to sham values and decreased cleaved caspase 3 by 46%, indicating attenuation of hemorrhage-induced apoptosis in the lungs. Hemorrhage resulted in significant reductions of β-catenin protein levels in the lungs as well as down-regulation of a Wnt target gene, cyclin D1, while Wnt agonist treatment preserved these levels.


CONCLUSIONS
The administration of Wnt agonist attenuated hemorrhage-induced organ injury, inflammation, and apoptosis. This was correlated with the preservation of the Wnt signaling pathway. Thus, Wnt/β-catenin activation could be protective in hemorrhagic shock.
From the Department of Surgery, (M.K., W.L.Y., A.J., A.K., M.G., J.N., G.F.C., P.W.), Hofstra North Shore-LIJ School of Medicine & Center for Translational Research, (W.L.Y., A.J., A.K., P.W.), Feinstein Institute for Medical Research.
Michael
M
Kuncewitch
Weng-Lang
WL
Yang
Asha
A
Jacob
Adam
A
Khader
Matthew
M
Giangola
Jeffrey
J
Nicastro
Gene F
GF
Coppa
Ping
P
Wang
D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D000077324:Crystalloid Solutions; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000188:drug therapy*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
C581356:2-amino-4-(3,4-(methylenedioxy)benzylamino)-6-(3-methoxyphenyl)pyrimidine; D052117:Benzodioxoles; D015415:Biomarkers; D000077324:Crystalloid Solutions; D015850:Interleukin-6; D007552:Isotonic Solutions; D011743:Pyrimidines; D009195:Peroxidase