Cardioprotective role of APIP in myocardial infarction through ADORA2B

Bitna Lim, Kwangmin Jung, Youngdae Gwon, Jae Gyun Oh, Jae il Roh, Se Hoon Hong, Changwon Kho, Woo Jin Park, Han Woong Lee, Jang Whan Bae, Yong Keun Jung

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number511
JournalCell Death and Disease
Volume10
Issue number7
DOIs
Publication statusPublished - 2019 Jul 1

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Adenosine A2B Receptors
Myocardial Infarction
Proteins
Ligation
Heart Injuries
Purinergic P1 Receptors
Immunoprecipitation
Cardiac Myocytes
Transgenic Mice
Single Nucleotide Polymorphism
Cell Death

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Lim, B., Jung, K., Gwon, Y., Oh, J. G., Roh, J. I., Hong, S. H., ... Jung, Y. K. (2019). Cardioprotective role of APIP in myocardial infarction through ADORA2B. Cell Death and Disease, 10(7), [511]. https://doi.org/10.1038/s41419-019-1746-3
Lim, Bitna ; Jung, Kwangmin ; Gwon, Youngdae ; Oh, Jae Gyun ; Roh, Jae il ; Hong, Se Hoon ; Kho, Changwon ; Park, Woo Jin ; Lee, Han Woong ; Bae, Jang Whan ; Jung, Yong Keun. / Cardioprotective role of APIP in myocardial infarction through ADORA2B. In: Cell Death and Disease. 2019 ; Vol. 10, No. 7.
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abstract = "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.",
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Lim, B, Jung, K, Gwon, Y, Oh, JG, Roh, JI, Hong, SH, Kho, C, Park, WJ, Lee, HW, Bae, JW & Jung, YK 2019, 'Cardioprotective role of APIP in myocardial infarction through ADORA2B', Cell Death and Disease, vol. 10, no. 7, 511. https://doi.org/10.1038/s41419-019-1746-3

Cardioprotective role of APIP in myocardial infarction through ADORA2B. / Lim, Bitna; Jung, Kwangmin; Gwon, Youngdae; Oh, Jae Gyun; Roh, Jae il; Hong, Se Hoon; Kho, Changwon; Park, Woo Jin; Lee, Han Woong; Bae, Jang Whan; Jung, Yong Keun.

In: Cell Death and Disease, Vol. 10, No. 7, 511, 01.07.2019.

Research output: Contribution to journalArticle

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T1 - Cardioprotective role of APIP in myocardial infarction through ADORA2B

AU - Lim, Bitna

AU - Jung, Kwangmin

AU - Gwon, Youngdae

AU - Oh, Jae Gyun

AU - Roh, Jae il

AU - Hong, Se Hoon

AU - Kho, Changwon

AU - Park, Woo Jin

AU - Lee, Han Woong

AU - Bae, Jang Whan

AU - Jung, Yong Keun

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

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