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Am J Hum Genet. 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008.

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension.

Author information

1
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2
School of Biomedical Sciences, the Chinese University of Hong Kong, Shatin, NT, Hong Kong.
3
School of Life Sciences, the Chinese University of Hong Kong, Hong Kong, Shatin, NT, Hong Kong.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Medicine - Cardiovascular Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
6
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
7
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
8
Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48823, USA.
9
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
10
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
11
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
13
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.

Abstract

Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.

KEYWORDS:

Mendelian forms of hypertension; angiogenesis; argininosuccinate lyase; argininosuccinic aciduria; endothelial cells; endothelial dysfunction; hypertension; induced pluripotent stem cells; nitric oxide; oxidative stress

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