Han Wei-Min, Chen Xu-Chang, Li Gui-Rong, Wang Yan
Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China.
Nanjing Amazigh Pharma Limited, Nanjing, China.
Front Pharmacol. 2020 Dec 18;11:607796. doi: 10.3389/fphar.2020.607796. eCollection 2020.
The strategy of decreasing atherosclerotic cardiovascular disorder is imperative for reducing premature death and improving quality of life in patients with diabetes mellitus. The aim of this study was to investigate whether the natural flavone acacetin could protect against endothelial injury induced by high glucose and attenuate diabetes-accelerated atherosclerosis in streptozotocin-(STZ) induced diabetic ApoE mice model. It was found that in human umbilical vein endothelial cells (HUVECs) cultured with normal 5.5 mM or high 33 mM glucose, acacetin (0.3-3 μM) exerted strong cytoprotective effects by reversing high glucose-induced viability reduction and reducing apoptosis and excess production of intracellular reactive oxygen species (ROS) and malondialdehyde in a concentration-dependent manner. Acacetin countered high glucose-induced depolarization of mitochondrial membrane potential and reduction of ATP product and mitoBcl-2/mitoBax ratio. Silencing Sirt3 abolished the beneficial effects of acacetin. Further analysis revealed that these effects of acacetin rely on Sirt1 activation by increasing NAD followed by increasing Sirt3, pAMPK and PGC-1α. In STZ-diabetic mice, acacetin significantly upregulated the decreased signaling molecules (i.e. SOD, Bcl-2, PGC-1α, pAMPK, Sirt3 and Sirt1) in aorta tissue and attenuated atherosclerosis. These results indicate that vascular endothelial protection of acacetin by activating Sirt1/Sirt3/AMPK signals is likely involved in alleviating diabetes-accelerated atherosclerosis by preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorder in patients with diabetes.
降低动脉粥样硬化性心血管疾病的策略对于降低糖尿病患者的过早死亡和改善生活质量至关重要。本研究的目的是调查天然黄酮刺槐素是否可以预防高糖诱导的内皮损伤，并减轻链脲佐菌素（STZ）诱导的糖尿病ApoE小鼠模型中糖尿病加速的动脉粥样硬化。研究发现，在正常5.5 mM或高33 mM葡萄糖培养的人脐静脉内皮细胞（HUVECs）中，刺槐素（0.3 - 3 μM）通过逆转高糖诱导的活力降低、减少细胞凋亡以及细胞内活性氧（ROS）和丙二醛的过量产生，以浓度依赖的方式发挥强大的细胞保护作用。刺槐素对抗高糖诱导的线粒体膜电位去极化、ATP产物减少以及mitoBcl-2/mitoBax比值降低。沉默Sirt3消除了刺槐素的有益作用。进一步分析表明，刺槐素的这些作用依赖于通过增加NAD激活Sirt1，随后增加Sirt3、pAMPK和PGC-1α。在STZ诱导的糖尿病小鼠中，刺槐素显著上调主动脉组织中降低的信号分子（即SOD、Bcl-2、PGC-1α、pAMPK、Sirt3和Sirt1）并减轻动脉粥样硬化。这些结果表明，刺槐素通过激活Sirt1/Sirt3/AMPK信号对血管内皮的保护作用可能参与通过维持线粒体功能来减轻糖尿病加速的动脉粥样硬化，这表明刺槐素可能是治疗糖尿病患者心血管疾病的候选药物。
