Genetic Deletion of the LINC00520 Homolog in Mouse Aggravates Angiotensin II-Induced Hypertension

Author:

Tang Xiaofang1,Lai Chih-Hung123ORCID,Malhi Naseeb K.1,Chadha Rahuljeet14,Luo Yingjun1,Liu Xuejing1,Yuan Dongqiang1,Tapia Alonso15,Abdollahi Maryam1,Zhang Guangyu6,Calandrelli Riccardo7ORCID,Shiu Yan-Ting89ORCID,Wang Zhao V.56ORCID,Rhee June-Wha10,Zhong Sheng7,Natarajan Rama15ORCID,Chen Zhen Bouman15

Affiliation:

1. Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA

2. Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan

3. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 40705, Taiwan

4. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91010, USA

5. Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA

6. Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes Metabolism Research Institute and Beckman Research Institute of City of Hope, Duarte, CA 91010, USA

7. Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA

8. Division of Nephrology & Hypertension, University of Utah, Salt Lake City, UT 84132, USA

9. Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT 84132, USA

10. Department of Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA

Abstract

(1) Background: Hypertension is a complex, multifactorial disease that is caused by genetic and environmental factors. Apart from genetic predisposition, the mechanisms involved in this disease have yet to be fully understood. We previously reported that LEENE (lncRNA enhancing endothelial nitric oxide expression, transcribed from LINC00520 in the human genome) regulates endothelial cell (EC) function by promoting the expression of endothelial nitric oxide synthase (eNOS) and vascular growth factor receptor 2 (VEGFR2). Mice with genetic deletion of the LEENE/LINC00520 homologous region exhibited impaired angiogenesis and tissue regeneration in a diabetic hindlimb ischemia model. However, the role of LEENE in blood pressure regulation is unknown. (2) Methods: We subjected mice with genetic ablation of leene and wild-type littermates to Angiotensin II (AngII) and monitored their blood pressure and examined their hearts and kidneys. We used RNA-sequencing to identify potential leene-regulated molecular pathways in ECs that contributed to the observed phenotype. We further performed in vitro experiments with murine and human ECs and ex vivo experiments with murine aortic rings to validate the select mechanism. (3) Results: We identified an exacerbated hypertensive phenotype of leene-KO mice in the AngII model, evidenced by higher systolic and diastolic blood pressure. At the organ level, we observed aggravated hypertrophy and fibrosis in the heart and kidney. Moreover, the overexpression of human LEENE RNA, in part, restored the signaling pathways impaired by leene deletion in murine ECs. Additionally, Axitinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR suppresses LEENE in human ECs. (4) Conclusions: Our study suggests LEENE as a potential regulator in blood pressure control, possibly through its function in ECs.

Funder

National Institutes of Health

California Institute of Regenerative Medicine

American Heart Association

National Cancer Institute of the NIH

Publisher

MDPI AG

Subject

Genetics,Molecular Biology,Biochemistry

Reference43 articles.

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4. Outcomes of Intensive Blood Pressure Lowering in Older Hypertensive Patients;Bavishi;J. Am. Coll. Cardiol.,2017

5. Understanding the role of genetics in hypertension;Patel;Eur. Heart J.,2017

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