Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction
| Autor: | Jiaxin Song, Joost P.G. Sluijter, Jiahong Xu, Yajun Liang, Junjie Xiao, Yujiao Zhu, Jiali Deng, Minjun Xu, Jianhua Yao, Danni Meng, Qiulian Zhou |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cardiac function curve
Adult medicine.medical_specialty Medicine (General) Research paper Human Embryonic Stem Cells Myocardial Infarction Down-Regulation HIPK2 Protein Serine-Threonine Kinases General Biochemistry Genetics and Molecular Biology Running Gene Knockout Techniques Mice R5-920 Downregulation and upregulation Internal medicine medicine Animals Humans Myocytes Cardiac Myocardial infarction Protein kinase A Exercise Cells Cultured Swimming Activator (genetics) business.industry General Medicine Dependovirus Middle Aged medicine.disease Infarct size miR-222 Rats Disease Models Animal MicroRNAs Animals Newborn Apoptosis Case-Control Studies Cardiology Medicine Oxygen glucose deprivation business Carrier Proteins |
| Zdroj: | EBioMedicine EBioMedicine, Vol 74, Iss, Pp 103713-(2021) |
| ISSN: | 2352-3964 8202-0108 |
| Popis: | Background Exercise can protect myocardial infarction (MI) and downregulate cardiac Homeodomain-Interacting Protein Kinase 2 (HIPK2). However, the role of HIPK2 in MI is unclear. Methods 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. Findings 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. Interpretation 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. Funding 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|