PDF(Pubmed)
Abstract：
Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy.
METHODS: We evaluated roxadustat\'s impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI.
RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling.
CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.
METHODS: We evaluated roxadustat\'s impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI.
RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling.
CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.
摘要：
已知CXCL12/CXCR4/ACKR3轴的激活通过缺血触发的缺氧诱导因子-1α(HIF-1α)帮助心肌修复。为了增强HIF-1α的上调，我们服用了罗沙司，一种由欧洲药品管理局2021年临床批准的用于治疗肾性贫血的新型脯氨酸酰羟化酶抑制剂（PHI），目的是改善左心室功能和减轻缺血性心肌病。
方法：我们评估了roxadustat对HIF-1刺激的影响，心脏重塑,并在MI后起作用。因此,我们分析了核HIF-1表达，HIF-1关键靶基因的mRNA和蛋白表达(RT-PCR，蛋白质印迹)，炎性细胞浸润（免疫组织化学），MI后7天和细胞凋亡(TUNEL染色)。此外,我们对雄性和雌性C57BL/6小鼠在MI后28天进行了超声心动图检查。
结果：我们发现细胞核HIF-1的显著增加，与HIF-1α靶基因如CXCL12/CXCR4/ACKR3在mRNA和蛋白质水平的上调有关。Roxadustat增加了心肌修复性M2CD206+细胞的比例，提示免疫细胞迁移的有益改变和凋亡减少的趋势。超声心动图显示罗沙司治疗可显着保留射血分数并减轻随后的心室扩张，从而减少不良重塑。
结论：我们的研究结果表明，罗沙司他是一种有希望的临床批准的治疗选择，通过减轻不良重塑来保持心肌功能。
方法：我们评估了roxadustat对HIF-1刺激的影响，心脏重塑,并在MI后起作用。因此,我们分析了核HIF-1表达，HIF-1关键靶基因的mRNA和蛋白表达(RT-PCR，蛋白质印迹)，炎性细胞浸润（免疫组织化学），MI后7天和细胞凋亡(TUNEL染色)。此外,我们对雄性和雌性C57BL/6小鼠在MI后28天进行了超声心动图检查。
结果：我们发现细胞核HIF-1的显著增加，与HIF-1α靶基因如CXCL12/CXCR4/ACKR3在mRNA和蛋白质水平的上调有关。Roxadustat增加了心肌修复性M2CD206+细胞的比例，提示免疫细胞迁移的有益改变和凋亡减少的趋势。超声心动图显示罗沙司治疗可显着保留射血分数并减轻随后的心室扩张，从而减少不良重塑。
结论：我们的研究结果表明，罗沙司他是一种有希望的临床批准的治疗选择，通过减轻不良重塑来保持心肌功能。
