DataSheet1_Honokiol Ameliorates Post-Myocardial Infarction Heart Failure Through Ucp3-Mediated Reactive Oxygen Species Inhibition.docx

Post-myocardial infarction heart failure (post-MI HF) is one of the leading global causes of death, and current prevention and treatment methods still cannot avoid the increasing incidence. Honokiol (HK) has previously been reported to improve myocardial ischemia/reperfusion injury and reverse myocardial hypertrophy by activating Sirt1 and Sirt3. We suspect that HK may also have a therapeutic effect on post-MI HF. In this study, we aimed to investigate the efficacy and mechanism of HK in the treatment of post-MI HF. We found that HK inhibited myocardial reactive oxygen species (ROS) production, reduced myocardial fibrosis, and improved cardiac function in mice after MI. HK also reduced the abnormality of mitochondrial membrane potential (MMP) and apoptosis of cardiomyocytes caused by peroxide in neonatal cardiomyocytes. RNAseq results revealed that HK restored the transcriptome changes to a certain extent and significantly enhanced the expression of mitochondrial inner membrane uncoupling protein isoform 3 (Ucp3), a protein that inhibits the production of mitochondrial ROS, protects cardiomyocytes, and relieves heart failure after myocardial infarction (MI). In cardiomyocytes with impaired Ucp3 expression, HK cannot protect against the damage caused by peroxide. More importantly, in Ucp3 knockout mice, HK did not change the increase in the ROS level and cardiac function damage after MI. Taken together, our results suggest that HK can increase the expression of the cardioprotective protein Ucp3 and maintain MMP, thereby inhibiting the production of ROS after MI and ameliorating heart failure.

心肌梗死后心力衰竭（post-MI HF）是全球主要致死病因之一，当前的预防与治疗手段仍无法遏制其发病率持续攀升的趋势。和厚朴酚（HK）既往研究显示可通过激活沉默信息调节因子1（Sirt1）与沉默信息调节因子3（Sirt3），改善心肌缺血/再灌注损伤并逆转心肌肥厚。我们推测HK或可对心肌梗死后心力衰竭发挥治疗作用。本研究旨在探究HK治疗心肌梗死后心力衰竭的疗效及其作用机制。研究结果表明，HK可抑制心肌梗死后小鼠的心肌活性氧（ROS）生成、减轻心肌纤维化并改善心功能。在新生心肌细胞实验中，HK还可缓解过氧化氢诱导的线粒体膜电位（MMP）异常与心肌细胞凋亡。RNA测序（RNAseq）结果显示，HK可在一定程度上恢复异常的转录组表达谱，并显著上调线粒体内膜解偶联蛋白亚型3（Ucp3）的表达——该蛋白可抑制线粒体活性氧生成、保护心肌细胞并缓解心肌梗死后心力衰竭。在Ucp3表达受损的心肌细胞中，HK无法抵御过氧化氢介导的细胞损伤。更为关键的是，在Ucp3基因敲除小鼠体内，HK未能改善心肌梗死后的ROS水平升高与心功能损伤。综上，本研究结果证实，HK可上调心脏保护性蛋白Ucp3的表达、维持线粒体膜电位，从而抑制心肌梗死后的活性氧生成并改善心力衰竭。