Aldose Reductase-Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction and Damage in Diabetic Platelets.
Tang, Wai Ho PhD; Stitham, Jeremiah MD, PhD; Jin, Yu MD, PhD; Liu, Renjing PhD; Lee, Seung Hee PhD; Du, Jing MD, PhD; Atteya, Gourg MD; Gleim, Scott PhD; Spollett, Geralyn MSN; Martin, Kathleen PhD; Hwa, John MD, PhD
129(15):1598-1609, April 15, 2014.
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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.
Methods and 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.
(C) 2014 by the American College of Cardiology Foundation and the American Heart Association, Inc.