Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction.
Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction.
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运动下调 HIPK2，抑制 HIPK2 可预防心肌梗塞
DOI：
10.1016/j.ebiom.2021.103713
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发表时间：
2021-12
期刊：
影响因子：
11.1
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Zhou Q;Deng J;Yao J;Song J;Meng D;Zhu Y;Xu M;Liang Y;Xu J;Sluijter JP;Xiao J
运动可保护心肌梗死，下调心肌同源域相互作用蛋白激酶2(HIPK2)的表达。然而，HIPK2在心肌梗死中的作用尚不清楚。HIPK2-/-小鼠和miR-222-/-大鼠、HIPK2抑制剂(PKI1H)和携带miR-222的腺相关病毒血清9(AAV9)用于研究。动物接受跑步、游泳、急性心肌梗死或心肌梗死后重塑。应用HIPK2抑制剂和P53激活剂对缺氧缺糖/再灌流(OGD/R)的新生大鼠心肌细胞(NRCM)和人胚胎干细胞来源的心肌细胞(hESC-CMS)进行研究。分析健康人和存活或再次入院和/或死亡的MI患者的血清miR-222水平。心肌HIPK2蛋白水平在运动后降低，而在心肌梗死时升高。在体外，慢病毒载体或抑制剂抑制HIPK2可阻止OGD/R诱导的NRCMS和hESC-CMS的凋亡。HIPK2抑制剂治疗的小鼠和HIPK2-/-小鼠在急性心肌梗死后缩小了梗死面积，并在心肌梗死重塑中保护了心功能。从机制上讲，抑制HIPK2对细胞凋亡的保护作用可被P53激活剂逆转。此外，针对HIPK2的miR-222水平的增加保护了MI后的心功能障碍，而MI后的心功能障碍在miR-222-/-大鼠中加重。此外，心肌梗死患者以及再次入院和/或死亡的心肌梗死患者的血清miR-222水平显著低于未入院的患者。运动诱导的HIPK2抑制可减少心肌细胞的凋亡，并通过降低P-P53来保护心肌梗死。抑制HIPK2代表了一种潜在的治疗MI的新的干预措施。本研究得到了国家重点研究发展计划(2018YFE0113500对肖进进)、国家自然科学基金中国(82020108002、81722008、81911540486对肖进进，81400647对徐明江、81800265对梁永健)、上海市教委创新计划(2017年01月-07-00-09-E00042对肖进进)、上海市科委资助(18410722200和17010500100对肖进进)、上海市教委“曙光”计划(19SG34到肖进进)、上海市帆船计划(21YF1413200对肖进进)的资助。JS由Horizon 2020 ERC-2016-COG EVICARE(725229)支持。
Exercise can protect myocardial infarction (MI) and downregulate cardiac Homeodomain-Interacting Protein Kinase 2 (HIPK2). However, the role of HIPK2 in MI is unclear. HIPK2–/– mice and miR-222–/– rats, HIPK2 inhibitor (PKI1H) and adeno-associated virus serotype 9 (AAV9) carrying miR-222 were applied in the study. Animals were subjected to running, swimming, acute MI or post-MI remodeling. HIPK2 inhibition and P53 activator were used in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) subjected to oxygen glucose deprivation/reperfusion (OGD/R). Serum miR-222 levels were analyzed in healthy people and MI patients that were survival or readmitted to the hospital and/or died. Cardiac HIPK2 protein levels were reduced by exercise while increased in MI. In vitro, HIPK2 suppression by lentiviral vectors or inhibitor prevented apoptosis induced by OGD/R in NRCMs and hESC-CMs. HIPK2 inhibitor-treated mice and HIPK2–/– mice reduced infarct size after acute MI, and preserved cardiac function in MI remodeling. Mechanistically, protective effect against apoptosis by HIPK2 suppression was reversed by P53 activators. Furthermore, increasing levels of miR-222, targeting HIPK2, protected post-MI cardiac dysfunction, whereas cardiac dysfunction post-MI was aggravated in miR-222–/– rats. Moreover, serum miR-222 levels were significantly reduced in MI patients, as well as in MI patients that were readmitted to the hospital and/or died compared to those not. Exercise-induced HIPK2 suppression attenuates cardiomyocytes apoptosis and protects MI by decreasing P-P53. Inhibition of HIPK2 represents a potential novel therapeutic intervention for MI. This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to JJ Xiao), National Natural Science Foundation of China (82020108002, 81722008, and 81911540486 to JJ Xiao, 81400647 to MJ Xu, 81800265 to YJ Liang), Innovation Program of Shanghai Municipal Education Commission (2017-01-07-00-09-E00042 to JJ Xiao), the grant from Science and Technology Commission of Shanghai Municipality (18410722200 and 17010500100 to JJ Xiao), the “Dawn” Program of Shanghai Education Commission (19SG34 to JJ Xiao), Shanghai Sailing Program (21YF1413200 to QL Zhou). JS is supported by Horizon2020 ERC-2016-COG EVICARE (725229).
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