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Apaf-1-interacting protein (<jats:italic>APIP)<\/jats:italic> and <jats:italic>ADORA2B<\/jats:italic> transcript levels in human hearts are substantially higher in patients with heart failure than in controls. Interestingly, the <jats:italic>APIP<\/jats:italic> and <jats:italic>ADORA2B<\/jats:italic> mRNA levels are highly correlated with each other (<jats:italic>R<\/jats:italic>\u2009=\u20090.912). 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-HIF1\u03b1 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 <jats:italic>APIP<\/jats:italic><jats:sup>Tg\/Tg<\/jats:sup>, <jats:italic>APIP<\/jats:italic><jats:sup>Tg\/+<\/jats:sup>, and <jats:italic>Apip<\/jats:italic><jats:sup>+\/-<\/jats:sup> 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, <jats:italic>Adora2b<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41419-019-1746-3","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T11:04:02Z","timestamp":1561979042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardioprotective role of APIP in myocardial infarction through ADORA2B"],"prefix":"10.1038","volume":"10","author":[{"given":"Bitna","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangmin","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngdae","family":"Gwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Gyun","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-il","family":"Roh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Hoon","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changwon","family":"Kho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo-Jin","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Woong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jang-Whan","family":"Bae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Keun","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,1]]},"reference":[{"key":"1746_CR1","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1161\/hc4601.099487","volume":"104","author":"S Yusuf","year":"2001","unstructured":"Yusuf, S., Reddy, S., Ounpuu, S. & Anand, S. 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