1. Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA 2 signaling.
- Author
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Wan R, Zhou J, Mao R, Zheng Y, Zhou F, Pan L, Hong Y, Jin L, Li S, and Zhu C
- Subjects
- Animals, Mice, Male, Humans, Female, Phospholipases A2, Cytosolic metabolism, Phospholipases A2, Cytosolic genetics, Reactive Oxygen Species metabolism, Mice, Inbred C57BL, Pyruvaldehyde metabolism, Apoptosis drug effects, Signal Transduction drug effects, Endothelial Cells metabolism, Endothelial Cells pathology, Endothelial Cells drug effects, Receptors, Androgen metabolism, Receptors, Androgen genetics, Coronary Vessels pathology, Coronary Vessels metabolism
- Abstract
Objective: Since diabetic patients with coronary microvascular dysfunction (CMD) exhibit high cardiac mortality and women have higher prevalence of non-obstructive coronary artery disease than men, we tried to expand the limited understanding about the etiology and the sex difference of diabetic CMD., Approach and Results: Accumulated methylglyoxal (MGO) due to diabetes promotes vascular damage and it was used for mimicking diabetic status. Flow cytometry analysis and isometric tension measurement were performed to evaluate coronary artery endothelial injury. MGO induced apoptosis of coronary endothelial cells, accompanied by downregulation of androgen receptor (AR). Lentivirus-mediated stable expression of AR in coronary endothelial cells increased anti-apoptotic Bcl-2 expression and attenuated MGO-induced cell apoptosis. cPLA
2 activation was the downstream of AR downregulation by MGO treatment. Moreover, MGO also activated cPLA2 rapidly to impair endothelium-dependent vasodilation of coronary arteries from mice. Reactive oxygen species (ROS) overproduction was demonstrated to account for MGO-mediated cPLA2 activation and endothelial dysfunction. Importantly, AR blockade increased endothelial ROS production whereas AR activation protected coronary artery endothelial vasodilatory function from the MGO-induced injury. Although galectin-3 upregulation was confirmed by siRNA knockdown in endothelial cells not to participate in MGO-induced endothelial apoptosis, pharmacological inhibitor of galectin-3 further enhanced MGO-triggered ROS generation and coronary artery endothelial impairment., Conclusions: Our data proposed the AR downregulation-ROS overproduction-cPLA2 activation pathway as one of the mechanisms underlying diabetic CMD and postulated a possible reason for the sex difference of CMD-related angina. Meanwhile, MGO-induced galectin-3 activation played a compensatory role against coronary endothelial dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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