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  3. Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA2 signaling

Methylglyoxal induces endothelial cell apoptosis and coronary microvascular dysfunction through regulating AR-cPLA2 signaling

  • Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167437. doi: 10.1016/j.bbadis.2024.167437.
Rong Wan 1,  Jun Zhou 2,  Rongchen Mao 3,  Yuhan Zheng 3,  Feier Zhou 3,  Lihua Pan 3,  Yali Hong 3,  Lai Jin 3,  Shengnan Li 3,  Chao Zhu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Jiangxi Key Laboratory of Molecular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Department of Clinical Pharmacy, Jinling Hospital, Affiliated Hospital of Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210002, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China. Electronic address: czhu@njmu.edu.cn.
PMID: 39067539 DOI: 10.1016/j.bbadis.2024.167437
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. cPLA2 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.

Keywords

Coronary microvascular dysfunction; Diabetes; Methylglyoxal; Sex difference; cPLA(2).

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