Benzhi Cai1, Wenya Ma2, Fengzhi Ding2, Lai Zhang2, Qi Huang2, Xiuxiu Wang2, Bingjie Hua2, Juan Xu3, Jiamin Li2, Chongwei Bi2, Shuyuan Guo4, Fan Yang2, Zhenbo Han2, Yuan Li2, Gege Yan2, Ying Yu2, Zhengyi Bao2, Meixi Yu2, Faqian Li5, Ye Tian4, Zhenwei Pan6, Baofeng Yang7. 1. Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China; Institute of Clinical Pharmacy, the Heilongjiang Key Laboratory of Drug Research, Harbin Medical University, Harbin, China. Electronic address: caibz@ems.hrbmu.edu.cn. 2. Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China. 3. Department of Bioinformatics, Harbin Medical University, Harbin, China. 4. Department of Cardiology at the First Affiliated Hospital, Harbin Medical University, Harbin, China. 5. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. 6. Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China. Electronic address: panzw@ems.hrbmu.edu.cn. 7. Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China. Electronic address: yangbf@ems.brbmu.edu.cn.
Abstract
BACKGROUND: Adult mammalian heart loses regeneration ability following ischemic injury due to the loss of cardiomyocyte mitosis. However, the molecular mechanisms underlying the post-mitotic nature of cardiomyocytes remain largely unknown. OBJECTIVES: The purpose of this study was to define the essential role of long noncoding ribonucleic acids (lncRNAs) in heart regeneration during postnatal and adult injury. METHODS: Myh6-driving cardiomyocyte-specific lncRNA-CAREL transgenic mice and adenovirus-mediated in vivo silencing of endogenous CAREL were used in this study. The effect of CAREL on cardiomyocyte replication and heart regeneration after apical resection or myocardial infarction was assessed by detecting mitosis and cytokinesis. RESULTS: An lncRNA CAREL was found significantly up-regulated in cardiomyocytes from neonatal mice (P7) in parallel with loss of regenerative capacity. Cardiac-specific overexpression of CAREL in mice reduced cardiomyocyte division and proliferation and blunted neonatal heart regeneration after injury. Conversely, silencing of CAREL in vivo markedly promoted cardiac regeneration and improved heart functions after myocardial infarction in neonatal and adult mice. CAREL acted as a competing endogenous ribonucleic acid for miR-296 to derepress the expression of Trp53inp1 and Itm2a, the target genes of miR-296. Consistently, overexpression of miR-296 significantly increased cardiomyocyte replication and cardiac regeneration after injury. Decline of cardiac regenerative ability in CAREL transgenic mice was also rescued by miR-296. A short fragment containing the conserved sequence of CAREL reduced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes as the full-length CAREL. CONCLUSIONS: LncRNA CAREL regulates cardiomyocyte proliferation and heart regeneration in postnatal and adult heart after injury by acting as a competing endogenous ribonucleic acid on miR-296 that targets Trp53inp1 and Itm2a.
BACKGROUND: Adult mammalian heart loses regeneration ability following ischemic injury due to the loss of cardiomyocyte mitosis. However, the molecular mechanisms underlying the post-mitotic nature of cardiomyocytes remain largely unknown. OBJECTIVES: The purpose of this study was to define the essential role of long noncoding ribonucleic acids (lncRNAs) in heart regeneration during postnatal and adult injury. METHODS:Myh6-driving cardiomyocyte-specific lncRNA-CAREL transgenic mice and adenovirus-mediated in vivo silencing of endogenous CAREL were used in this study. The effect of CAREL on cardiomyocyte replication and heart regeneration after apical resection or myocardial infarction was assessed by detecting mitosis and cytokinesis. RESULTS: An lncRNA CAREL was found significantly up-regulated in cardiomyocytes from neonatal mice (P7) in parallel with loss of regenerative capacity. Cardiac-specific overexpression of CAREL in mice reduced cardiomyocyte division and proliferation and blunted neonatal heart regeneration after injury. Conversely, silencing of CAREL in vivo markedly promoted cardiac regeneration and improved heart functions after myocardial infarction in neonatal and adult mice. CAREL acted as a competing endogenous ribonucleic acid for miR-296 to derepress the expression of Trp53inp1 and Itm2a, the target genes of miR-296. Consistently, overexpression of miR-296 significantly increased cardiomyocyte replication and cardiac regeneration after injury. Decline of cardiac regenerative ability in CAREL transgenic mice was also rescued by miR-296. A short fragment containing the conserved sequence of CAREL reduced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes as the full-length CAREL. CONCLUSIONS: LncRNA CAREL regulates cardiomyocyte proliferation and heart regeneration in postnatal and adult heart after injury by acting as a competing endogenous ribonucleic acid on miR-296 that targets Trp53inp1 and Itm2a.