LKB1 suppression promotes cardiomyocyte regeneration via LKB1-AMPK-YAP axis

Shuang Qu; Qiao  Liao; Cheng Yu; Yue Chen; Han Luo; Xuewei Xia; Duofen He; Zaicheng Xu; Pedro A. Jose; Zhuxin Li; Wei Eric Wang; Qing Rex Lyu; Chunyu Zeng

doi:10.17305/bjbms.2021.7225

Authors

Shuang Qu Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China https://orcid.org/0000-0002-1780-8327
Qiao Liao Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Cheng Yu Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Yue Chen Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Han Luo Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Xuewei Xia Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Duofen He Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Zaicheng Xu Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Pedro A. Jose Division of Renal Diseases and Hypertension, Departments of Medicine and Pharmacology/Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
Zhuxin Li Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Wei Eric Wang Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China
Qing Rex Lyu Biomedical and Health Institute, Chongqing Institute of Green and Intelligence Technology, Chinese Academy of Sciences, Chongqing, China; Cardiovascular Research Center of Chongqing College, University of Chinese Academy of Sciences, Chongqing, China
Chunyu Zeng Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, China; Cardiovascular Research Center of Chongqing College, University of Chinese Academy of Sciences, Chongqing, China

DOI:

https://doi.org/10.17305/bjbms.2021.7225

Keywords:

LKB1, cardiomyocyte proliferation, AMPK, YAP

Abstract

The regenerative potential of cardiomyocytes in adult mammals is limited. Previous studies reported that cardiomyocyte proliferation is suppressed by AMP-activated protein kinase (AMPK). The role of liver kinase B1 (LKB1), as the major upstream kinase for AMPK, on cardiomyocyte proliferation is unclear. In this study, we found that the LKB1 levels rapidly increased after birth. With loss- and gain-of-function study, our data demonstrated that LKB1 levels negatively correlate with cardiomyocyte proliferation. We next identified Yes-associated protein (YAP) as the downstream effector of LKB1 using high-throughput RNA sequencing. Our results also demonstrated that AMPK plays an essential role in Lkb1 knockdown-induced cardiomyocyte proliferation. Importantly, deactivated AMPK abolished the LKB1-mediated regulation of YAP nuclear translocation and cardiomyocyte proliferation. Thus, our findings suggested the role of LKB1-AMPK-YAP axis during cardiomyocyte proliferation, which could be used as a potential target for inducing cardiac regeneration after injury.