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.
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.
Bosn J Basic Med Sci. 2022 Sep 16;22(5):772-783. doi: 10.17305/bjbms.2021.7225.
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.
成年哺乳动物心肌细胞的再生潜力有限。先前的研究表明，AMP 激活的蛋白激酶 (AMPK) 抑制心肌细胞增殖。作为 AMPK 的主要上游激酶，肝激酶 B1 (LKB1) 在心肌细胞增殖中的作用尚不清楚。在这项研究中，我们发现 LKB1 水平在出生后迅速增加。通过失活和功能获得研究，我们的数据表明 LKB1 水平与心肌细胞增殖呈负相关。接下来，我们使用高通量 RNA 测序鉴定出 YAP 是 LKB1 的下游效应物。我们的结果还表明，AMPK 在 Lkb1 敲低诱导的心肌细胞增殖中起重要作用。重要的是，失活的 AMPK 消除了 LKB1 介导的 YAP 核易位和心肌细胞增殖的调节。因此，我们的研究结果表明 LKB1-AMPK-YAP 轴在心肌细胞增殖中的作用，可作为损伤后诱导心脏再生的潜在靶点。
