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l-Leucine and NO-mediated cardiovascular function

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Abstract

Reduced availability of nitric oxide (NO) in the vasculature is a major factor contributing to the impaired action of insulin on blood flow and, therefore, insulin resistance in obese and diabetic subjects. Available evidence shows that vascular insulin resistance plays an important role in the pathogenesis of cardiovascular disease, the leading cause of death in developed nations. Interestingly, increased concentrations of l-leucine in the plasma occur in obese humans and other animals with vascular dysfunction. Among branched-chain amino acids, l-leucine is unique in inhibiting NO synthesis from l-arginine in endothelial cells and may modulate cardiovascular homeostasis in insulin resistance. Results of recent studies indicate that l-leucine is an activator of glutamine:fructose-6-phosphate aminotransferase (GFAT), which is the first and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, l-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells. We propose that reducing circulating levels of l-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects. Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of l-leucine in the small intestine and other tissues or with N-ethyl-l-glutamine to inhibit GFAT activity in endothelial cells. Preventing leucine-induced activation of GFAT by nutritional supplements or pharmaceutical drugs may contribute to improved cardiovascular function by enhancing vascular NO synthesis.

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Abbreviations

BCAA:

Branched-chain amino acids

BCAT:

Branched-chain amino acid transaminase

BCKAD:

Branched-chain α-ketoacid dehydrogenase

BH4:

(6R)-5,6,7,8-Tetrahydro-l-biopterin

EDCF:

Endothelium-derived constricting factor

EDRF:

Endothelium-derived relaxing factor

FAD:

Flavin adenine dinucleotide

FMN:

Flavin mononucleotide

GFAT:

Glutamine:fructose-6-phosphate aminotransferase

KIC:

α-Ketoisocaproate

mTOR:

Mammalian target of rapamycin

NADPH:

Nicotinamide adenine dinucleotide phosphate

NO:

Nitric oxide

NOS:

Nitric oxide synthase

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Acknowledgments

Work in our laboratories was supported by the National Basic Research Program of China (Grant 2013CB127302), the National Natural Science Foundation of China (No. 31172217, 31272451 and 31272450), American Heart Association (10GRNT4480020), and Texas A&M AgriLife Research (H-8200). Ying Yang was supported by a Fellowship from the Chinese Scholarship Council and National Natural Science Foundation of China (No. 31172225 and 31372327).

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  1. State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, People’s Republic of China

    Ying Yang, Zhenlong Wu & Guoyao Wu

  2. Department of Medical Physiology, Texas A&M University, College Station, TX, 77843, USA

    Ying Yang, Cynthia J. Meininger & Guoyao Wu

  3. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

    Guoyao Wu

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Yang, Y., Wu, Z., Meininger, C.J. et al. l-Leucine and NO-mediated cardiovascular function. Amino Acids 47, 435–447 (2015). https://doi.org/10.1007/s00726-014-1904-y

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  • DOI: https://doi.org/10.1007/s00726-014-1904-y

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