Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets.
BACKGROUND
Platelet abnormalities are well-recognized complications of diabetes mellitus. Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in diabetes mellitus. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in platelets in diabetes mellitus is unknown.


RESULTS
Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase activation and subsequent reactive oxygen species production lead to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage, and rupture by sequestration of the antiapoptotic protein Bcl-xL. In a glucose dose-dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation, and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, aldose reductase activation, reactive oxygen species production, and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are 2 distinct states that depend on the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model.


CONCLUSIONS
Aldose reductase contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for thrombotic complications in diabetes mellitus.
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine (W.H.T., J.S., Y.J., R.L., S.H.L., J.D., G.A., S.G., K.M., J.H.) and Section of Endocrinology and Metabolism, Department of Internal Medicine (G.S.), Yale University School of Medicine, New Haven, CT.
Wai Ho
WH
Tang
Jeremiah
J
Stitham
Yu
Y
Jin
Renjing
R
Liu
Seung Hee
SH
Lee
Jing
J
Du
Gourg
G
Atteya
Scott
S
Gleim
Geralyn
G
Spollett
Kathleen
K
Martin
John
J
Hwa
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C484670:AKR1B1 protein, human; C066498:Akr1b7 protein, mouse; D000449:Aldehyde Reductase
aldose reductase; apoptosis; diabetes mellitus; mitochondria; platelets