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.
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.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167437. doi: 10.1016/j.bbadis.2024.167437. Epub 2024 Jul 25.
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.
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 activation was the downstream of AR downregulation by MGO treatment. Moreover, MGO also activated cPLA rapidly to impair endothelium-dependent vasodilation of coronary arteries from mice. Reactive oxygen species (ROS) overproduction was demonstrated to account for MGO-mediated cPLA 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.
Our data proposed the AR downregulation-ROS overproduction-cPLA 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.
由于患有冠状动脉微血管功能障碍 (CMD) 的糖尿病患者的心脏死亡率较高，且女性患非阻塞性冠状动脉疾病的比例高于男性，因此我们试图扩展对糖尿病性 CMD 的病因和性别差异的有限认识。
由于糖尿病导致的累积甲基乙二醛 (MGO) 促进了血管损伤，因此我们用其来模拟糖尿病状态。通过流式细胞术分析和等长张力测量来评估冠状动脉内皮损伤。MGO 诱导冠状动脉内皮细胞凋亡，同时下调雄激素受体 (AR)。在冠状动脉内皮细胞中，通过慢病毒介导的 AR 稳定表达，增加了抗凋亡的 Bcl-2 表达，并减轻了 MGO 诱导的细胞凋亡。cPLA 的激活是 MGO 处理后 AR 下调的下游事件。此外，MGO 还可迅速激活 cPLA，从而损害来自小鼠的冠状动脉内皮依赖性血管舒张功能。研究表明，活性氧 (ROS) 的过度产生是 MGO 介导的 cPLA 激活和内皮功能障碍的原因。重要的是，AR 阻断增加了内皮细胞中的 ROS 产生，而 AR 激活则保护了冠状动脉内皮的血管舒张功能免受 MGO 诱导的损伤。尽管通过内皮细胞中的 siRNA 敲低证实了半乳糖凝集素-3 (Galectin-3) 的上调不参与 MGO 诱导的内皮细胞凋亡，但 Galectin-3 的药理学抑制剂进一步增强了 MGO 触发的 ROS 生成和冠状动脉内皮损伤。
我们的数据提出了 AR 下调-ROS 过度产生-cPLA 激活途径作为糖尿病性 CMD 的发病机制之一，并推测了 CMD 相关心绞痛的性别差异的可能原因。同时，MGO 诱导的 Galectin-3 激活在对抗冠状动脉内皮功能障碍方面发挥了代偿作用。
