Cardioprotective role of APIP in myocardial infarction through ADORA2B
| Autor: | Kwangmin Jung, Jang Whan Bae, Bitna Lim, Woo Jin Park, Jae Il Roh, Changwon Kho, Jae Gyun Oh, Youngdae Gwon, Yong-Keun Jung, Se Hoon Hong, Han Woong Lee |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse Cancer Research medicine.medical_specialty Immunology Myocardial Infarction Apoptosis Mice Transgenic Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Receptor Adenosine A2B Polymorphism Single Nucleotide Article Cell Line Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Internal medicine Animals Humans Medicine Myocytes Cardiac Myocardial infarction lcsh:QH573-671 Cells Cultured Mice Knockout Cardioprotection Gene knockdown Polymorphism Genetic lcsh:Cytology business.industry Myocardium Cell Biology medicine.disease Circulation HEK293 Cells 030104 developmental biology Endocrinology Heart failure Female Signal transduction Apoptosis Regulatory Proteins business Ligation Adenosine A2B receptor HeLa Cells Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 10, Iss 7, Pp 1-13 (2019) |
| ISSN: | 2041-4889 |
| Popis: | In ischemic human hearts, the induction of adenosine receptor A2B (ADORA2B) is associated with cardioprotection against ischemic heart damage, but the mechanism underlying this association remains unclear. Apaf-1-interacting protein (APIP) and ADORA2B transcript levels in human hearts are substantially higher in patients with heart failure than in controls. Interestingly, the APIP and ADORA2B mRNA levels are highly correlated with each other (R = 0.912). APIP expression was significantly increased in primary neonatal cardiomyocytes under hypoxic conditions and this induction reduced myocardial cell death via the activation of the AKT-HIF1α pathway. Accordingly, infarct sizes of APIP transgenic mice after left anterior descending artery ligation were significantly reduced compared to those of wild-type mice. Strikingly, knockdown of APIP expression impaired the cytoprotective effects of ADORA2B during hypoxic damage. Immunoprecipitation and proximity ligation assays revealed that APIP interacts with ADORA2B, leading to the stabilization of both proteins by interfering with lysosomal degradation, and to the activation of the downstream PKA-CREB signaling pathways. ADORA2B levels in the hearts of APIPTg/Tg, APIPTg/+, and Apip+/- mice were proportionally downregulated. In addition, ADORA2B D296G derived from the rs200741295 polymorphism failed to bind to APIP and did not exert cardioprotective activity during hypoxia. Moreover, Adora2b D296G knock-in mice were more vulnerable than control mice to myocardial infarction and intentional increases in APIP levels overcame the defective protection of the ADORA2B SNP against ischemic injury. Collectively, APIP is crucial for cardioprotection against myocardial infarction by virtue of binding to and stabilizing ADORA2B, thereby dampening ischemic heart injury. |
| Databáze: | OpenAIRE |
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