丹皮酚对阿霉素诱导的慢性心力衰竭的心脏保护作用：调控miR-21-5p/细胞周期蛋白依赖性激酶5调节亚基2轴
Cardioprotective Effect of Paeonol on Chronic Heart Failure Induced by Doxorubicin Regulating the miR-21-5p/S-Phase Kinase-Associated Protein 2 Axis.
作者信息
Chen Cong, Liu Shuhong, Cao Gaozhen, Hu Yang, Wang Run, Wu Min, Liu Mingya, Yiu Kai Hang
机构信息
Division of Cardiology, Department of Medicine, The University of Hong Kong, Shenzhen Hospital, Shenzhen, China.
Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Shenzhen, China.
出版信息
Front Cardiovasc Med. 2022 Jul 5;9:695004. doi: 10.3389/fcvm.2022.695004. eCollection 2022.
BACKGROUND
This study primarily explored the role of paeonol in doxorubicin (DOX)-induced chronic heart failure (CHF), considering the cardioprotective effect of paeonol on an epirubicin-induced cardiac injury.
METHODS
DOX-induced CHF-modeled rats were treated with paeonol. Cardiac function and myocardial damage in rats were evaluated by using the multifunction instrument, and the histopathology, apoptosis, and the expression of miR-21-5p and S-phase kinase-associated protein 2 (SKP2) in myocardium were detected. The target gene of miR-21-5p was confirmed by a dual-luciferase reporter assay. After the required transfection or paeonol treatment, the viability, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) of the DOX-induced cardiomyocytes were determined. Reverse-transcription quantitative-PCR (RT-qPCR) and Western blot were performed to quantify the expressions of miR-21-5p, SKP2, and apoptosis-related factors.
RESULTS
Paeonol improved cardiac function and also ameliorated the cardiac damage of CHF-modeled rats, where the downregulation of abnormally elevated myocardial damage markers, including brain natriuretic peptide, lactate dehydrogenase, renin, angiotensin II, aldosterone, and endothelin 1, was observed. Paeonol alleviated the histopathological injury and suppressed the apoptosis in CHF-modeled rats, inhibited miR-21-5p expression, and upregulated SKP2 expression and . miR-21-5p targeted SKP2. Paeonol and SKP2 increased the viability and MMP, but reduced apoptosis and ROS in the DOX-induced cardiomyocytes. miR-21-5p exerted effects opposite to PAE and SKP2, and it downregulated the expression of Bcl-2 and mitochondrion-Cytochrome c (Cyt c) and upregulated the expression of Bax, C-caspase-3, and cytoplasm-Cyt c. miR-21-5p reversed the effects of paeonol, and its effects were further reversed by SKP2.
CONCLUSION
Paeonol shows a cardioprotective effect on DOX-induced CHF regulating the miR-21-5p/SKP2 axis.
背景
鉴于丹皮酚对表柔比星诱导的心脏损伤具有心脏保护作用，本研究主要探讨丹皮酚在阿霉素（DOX）诱导的慢性心力衰竭（CHF）中的作用。
方法
用丹皮酚处理DOX诱导的CHF模型大鼠。使用多功能仪器评估大鼠的心功能和心肌损伤，并检测心肌的组织病理学、细胞凋亡以及miR-21-5p和S期激酶相关蛋白2（SKP2）的表达。通过双荧光素酶报告基因检测法确认miR-21-5p的靶基因。在进行所需的转染或丹皮酚处理后，测定DOX诱导的心肌细胞的活力、细胞凋亡、线粒体膜电位（MMP）和活性氧（ROS）。进行逆转录定量PCR（RT-qPCR）和蛋白质免疫印迹法以量化miR-21-5p、SKP2和凋亡相关因子的表达。
结果
丹皮酚改善了心功能，减轻了CHF模型大鼠的心脏损伤，观察到包括脑钠肽、乳酸脱氢酶、肾素、血管紧张素II、醛固酮和内皮素1在内的异常升高的心肌损伤标志物下调。丹皮酚减轻了CHF模型大鼠的组织病理学损伤并抑制了细胞凋亡，抑制了miR-21-5p表达，并上调了SKP2表达。miR-21-5p靶向SKP2。丹皮酚和SKP2增加了DOX诱导的心肌细胞的活力和MMP，但减少了细胞凋亡和ROS。miR-21-5p发挥了与PAE和SKP2相反的作用，它下调了Bcl-2和线粒体细胞色素c（Cyt c）的表达，并上调了Bax、C-半胱天冬酶-3和细胞质Cyt c的表达。miR-21-5p逆转了丹皮酚的作用，而SKP2进一步逆转了其作用。
结论
丹皮酚通过调节miR-21-5p/SKP2轴对DOX诱导的CHF具有心脏保护作用。
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