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01-05-2020 | Original Contribution

CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly

Authors: Yuanbin Li, Pengfei Liang, Bimei Jiang, Yuting Tang, Xuanyou Liu, Meidong Liu, Hui Sun, Cheng Chen, Hong Hao, Zhenguo Liu, Xianzhong Xiao

Published in: Basic Research in Cardiology | Issue 3/2020

Abstract

Autophagy in cardiomyocyte is involved in myocardial ischemia/reperfusion (M-I/R) injury. Caspase recruitment domain-containing protein 9 (CARD9) plays a critical role in cardiovascular diseases (CVDs) such as hypertension and cardiac fibrosis. However, its role in autophagy following M-I/R injury is yet to be fully elucidated. Here, we found that CARD9 expression increased in M-I/R mouse hearts, and in H9c2 or neonatal rat ventricular myocytes (NRVMs) in response to hypoxia/reoxygenation (H/R) or H₂O₂. CARD9^−/− mice exhibited a significant cardiac dysfunction following M-I/R injury (30 min of left ascending coronary (LAD) ischemia and 12 h of reperfusion) compared to wild-type (WT) mice. CARD9 deletion impaired autophagy during M-I/R in vivo and in vitro, evidenced by decrease of microtubule-associated protein 1 light chain 3 (LC3) lipidation and p62 accumulation. Conversely, CARD9 overexpression increased autophagic flux as indicated by enhanced expression of LC3 II/LC3 I and a reduction in p62. The protective effect of CARD9 on cardiomyocytes against H/R-induced oxidative stress was abolished by treatment with autophagy inhibitors, 3-methyladenine (3-MA) or Bafilomycin A1(BafA1). CARD9 interacted with RUN domain Beclin-1-interacting cysteine-rich-containing (Rubicon), a negative regulator of autophagy, and enhanced UV-irradiation-resistance-associated gene (UVRAG)-Beclin1-phosphatidylinositol 3-kinase catalytic subunit type 3 (PI3KC3) interaction and UVRAG-Vps16-mediated Rab7 activation to promote autophagosome formation, maturation, and endocytosis. Ablation of Rubicon by siRNA effectively prevented the detrimental effect of CARD9 knockdown on cardiomyocytes. These results suggest that CARD9 has protective effects on the myocardium against M-I/R injury by activating autophagy and restoring autophagic flux in vivo and in vitro.

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Title: CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly
Authors: Yuanbin Li
Pengfei Liang
Bimei Jiang
Yuting Tang
Xuanyou Liu
Meidong Liu
Hui Sun
Cheng Chen
Hong Hao
Zhenguo Liu
Xianzhong Xiao
Publication date: 01-05-2020
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2020
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-020-0790-6

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CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly

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