Malate and Aspartate Increase L-Arginine and Nitric Oxide and Attenuate Hypertension

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Entai Hou, Na Sun, Fuchang Zhang, Chenyang Zhao, Kristie Usa, Mingyu Liang, Zhongmin Tian
Fumarase catalyzes the interconversion of fumarate and L-malate in the tricarboxylic acid cycle. The Dahl salt-sensitive (SS) rat, a model of salt-sensitive hypertension, exhibits fumarase insufficiencies. To investigate the mechanism mediating the effect of fumarase-related metabolites on hypertension, we considered the pathway in which L-malate can be converted to oxaloacetate, aspartate, argininosuccinate, and L-arginine, the substrate of nitric oxide (NO) synthase. The levels of aspartate, citrulline, L-arginine, and NO were significantly decreased in the kidneys of SS rats compared to salt-insensitive consomic SS.13^BN rats. Knockdown of fumarase in human kidney cells and vascular endothelial cells resulted in decreased levels of malate, aspartate, L-arginine, and NO. Supplementation of aspartate or malate increased renal levels of L-arginine and NO and attenuated hypertension in SS rats. These findings reveal a multi-step metabolic pathway important for hypertension in which malate and aspartate may modulate blood pressure by altering levels of L-arginine and NO.

Graphical abstract

Teaser

Hou et al. discovered a multi-step metabolic pathway involved in the regulation of blood pressure in a model of salt-sensitive hypertension. In this pathway, fumarase insufficiencies and lower levels of malate result in decreased levels of aspartate, leading to decreased L-arginine regeneration and NO production and contributing to hypertension.


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