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Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Jordan Kho1, Xiaoyu Tian2, Wing-Tak Wong3

  • 1Program 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.

American Journal of Human Genetics
|August 4, 2018
PubMed

Insights

Argininosuccinate lyase deficiency (ASLD) causes a rare form of hypertension linked to endothelial dysfunction. This study reveals how ASLD impacts nitric oxide production and blood pressure regulation.

Area of Science:

  • Cardiovascular Science
  • Genetics
  • Metabolic Disorders

Background:

  • Primary hypertension is a significant risk factor for cardiovascular and kidney diseases.
  • Mendelian hypertension studies offer insights into primary hypertension mechanisms and treatments.
  • Endothelial cells are crucial for blood pressure regulation, but a Mendelian hypertension linked to endothelial dysfunction was undescribed.

Purpose of the Study:

  • To identify a Mendelian form of hypertension primarily caused by endothelial dysfunction.
  • To investigate the role of argininosuccinate lyase (ASL) in endothelial function and blood pressure.
  • To establish argininosuccinate lyase deficiency (ASLD) as a model for endothelial-dependent hypertension.

Main Methods:

  • Clinical data from human patients with ASLD.
  • Development and analysis of a mouse model with endothelial-specific deletion of Asl.
  • In vitro studies using human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from ASLD individuals.

Main Results:

  • ASLD manifests as a Mendelian form of endothelial-dependent hypertension.
  • Loss of ASL in endothelial cells causes vascular dysfunction, reduced nitric oxide (NO) production, and increased oxidative stress.
  • Impaired angiogenesis was observed in the ASL-deficient endothelial cells.

Conclusions:

  • ASLD represents a novel Mendelian form of hypertension driven by endothelial dysfunction.
  • The study highlights the critical role of ASL in maintaining endothelial health and vascular homeostasis.
  • ASLD provides a unique human model for investigating nitric oxide-dependent endothelial dysfunction in hypertension.

Keywords:
Mendelian forms of hypertensionangiogenesisargininosuccinate lyaseargininosuccinic aciduriaendothelial cellsendothelial dysfunctionhypertensioninduced pluripotent stem cellsnitric oxideoxidative stress

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