@article{e2c4f143b3444a18b4086c9e93cbe699,
title = "Long noncoding RNA LEENE promotes angiogenesis and ischemic recovery in diabetes models",
abstract = "Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response. LEENE expression was decreased in diabetic conditions in cultured endothelial cells (ECs), mouse hind limb muscles, and human arteries. Inhibition of LEENE in human microvascular ECs reduced their angiogenic capacity with a dysregulated angiogenic gene program. Diabetic mice deficient in Leene demonstrated impaired angiogenesis and perfusion following hind limb ischemia. Importantly, overexpression of human LEENE rescued the impaired ischemic response in Leene-knockout mice at tissue functional and single-cell transcriptomic levels. Mechanistically, LEENE RNA promoted transcription of proangiogenic genes in ECs, such as KDR (encoding VEGFR2) and NOS3 (encoding eNOS), potentially by interacting with LEO1, a key component of the RNA polymerase II–associated factor complex and MYC, a crucial transcription factor for angiogenesis. Taken together, our findings demonstrate an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis for tissue repair and regeneration may represent a potential strategy to tackle ischemic vascular diseases.",
author = "Xiaofang Tang and Yingjun Luo and Dongqiang Yuan and Riccardo Calandrelli and Malhi, {Naseeb Kaur} and Kiran Sriram and Yifei Miao and Lou, {Chih Hong} and Walter Tsark and Alonso Tapia and Chen, {Aleysha T.} and Guangyu Zhang and Daniel Roeth and Markus Kalkum and Wang, {Zhao V.} and Shu Chien and Rama Natarajan and Cooke, {John P.} and Sheng Zhong and Chen, {Zhen Bouman}",
note = "Funding Information: The authors thank Ismail Al-Abdullah and Meirigeng Qi of the islet transplantation team at City of Hope for isolation of human arteries, Xuejing Liu at City of Hope for technical assistance, and Patrick Fueger and June-Hwa Rhee at City of Hope, John Y-J. Shyy at UCSD, and Ming He at the University of Alabama Birmingham for helpful discussion and valuable inputs. This study was funded in part by grants from the NIH (R01 HL145170 to ZBC and JPC, DP1DK126138 and R01GM138852 to SZ, UG3 CA256960 to SZ and ZBC, R01 HL108735 to SC, JYS, and ZBC, R01 HL133254 to JPC, R01 HL106089 to RN and ZBC, R01GM141096 to ZBC, and R01DK065073 to RN), a seed network grant from Chan Zucker-berg Foundation (CZF2019-002444 to ZBC and SZ), Ella Fitzgerald Foundation (to ZBC), and California Institute of Regenerative Medicine grant EDU4-12772 (to AT). Research reported in this publication included work performed in the Integrative Genomics, Light Microscopy and Digital Imaging, Comprehensive Metabolic Phenotyping, and Pathology Cores supported by the National Cancer Institute of the NIH under award number P30CA033572. Funding Information: The authors thank Ismail Al-Abdullah and Meirigeng Qi of the islet transplantation team at City of Hope for isolation of human arteries, Xuejing Liu at City of Hope for technical assistance, and Patrick Fueger and June-Hwa Rhee at City of Hope, John Y-J. Shyy at UCSD, and Ming He at the University of Alabama Birmingham for helpful discussion and valuable inputs. This study was funded in part by grants from the NIH (R01 HL145170 to ZBC and JPC, DP1DK126138 and R01GM138852 to SZ, UG3 CA256960 to SZ and ZBC, R01 HL108735 to SC, JYS, and ZBC, R01 HL133254 to JPC, R01 HL106089 to RN and ZBC, R01GM141096 to ZBC, and R01DK065073 to RN), a seed network grant from Chan Zuckerberg Foundation (CZF2019-002444 to ZBC and SZ), Ella Fitzgerald Foundation (to ZBC), and California Institute of Regenerative Medicine grant EDU4-12772 (to AT). Research reported in this publication included work performed in the Integrative Genomics, Light Microscopy and Digital Imaging, Comprehensive Metabolic Phenotyping, and Pathology Cores supported by the National Cancer Institute of the NIH under award number P30CA033572. Publisher Copyright: {\textcopyright} 2023, Tang et al.",
year = "2023",
month = feb,
day = "1",
doi = "10.1172/JCI161759",
language = "English (US)",
volume = "133",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "3",
}