The Emerging Role of l-Glutamine in Cardiovascular Health and Disease

Abstract

Emerging evidence indicates that l-glutamine (Gln) plays a fundamental role in cardiovascular physiology and pathology. By serving as a substrate for the synthesis of DNA, ATP, proteins, and lipids, Gln drives critical processes in vascular cells, including proliferation, migration, apoptosis, senescence, and extracellular matrix deposition. Furthermore, Gln exerts potent antioxidant and anti-inflammatory effects in the circulation by inducing the expression of heme oxygenase-1, heat shock proteins, and glutathione. Gln also promotes cardiovascular health by serving as an l-arginine precursor to optimize nitric oxide synthesis. Importantly, Gln mitigates numerous risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, glucose intolerance, obesity, and diabetes. Many studies demonstrate that Gln supplementation protects against cardiometabolic disease, ischemia-reperfusion injury, sickle cell disease, cardiac injury by inimical stimuli, and may be beneficial in patients with heart failure. However, excessive shunting of Gln to the Krebs cycle can precipitate aberrant angiogenic responses and the development of pulmonary arterial hypertension. In these instances, therapeutic targeting of the enzymes involved in glutaminolysis such as glutaminase-1, Gln synthetase, glutamate dehydrogenase, and amino acid transaminase has shown promise in preclinical models. Future translation studies employing Gln delivery approaches and/or glutaminolysis inhibitors will determine the success of targeting Gln in cardiovascular disease.

Keywords: Krebs cycle; ammonia; cardiovascular disease; l-glutamate; l-glutamine; metabolism.

Figure 1

Overview of l-glutamine (Gln) transport and metabolism. Gln is transported into cells by various transporters and preferentially metabolized to l-glutamate (Glu) and ammonia (NH₃) by the mitochondrial enzyme glutaminase (GLS). In contrast, the enzyme glutamine synthetase (GS) condenses NH₃ to Glu to form Gln while the enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT) transfers Gln’s amino group to fructose-6-phosphate to generate glucosamine-6-phosphate. Gln and Glu can be converted to a number of important molecules, including amino acids, fatty acids, nucleotides, adenosine triphosphate (ATP), glutathione, and Krebs cycle intermediates. Asn, asparagine; ASNS, asparagine synthetase; Asp, aspartate; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; Cit, citrate; GLUD, glutamate dehydrogenase; αKG, α-ketoglutarate; Mal, malate; ME, malic enzyme; mTOR, mammalian target of rapamycin; NEAA, nonessential amino acids; NO, nitric oxide; OAA, oxaloacetate; Pyr, pyruvate; TAs, transaminases.

Figure 2

Role of l-glutamine (Gln)-derived ammonia (NH₃) in stimulating endothelial cell heme oxygenase-1 (HO-1) gene expression and maintaining vascular homeostasis. Gln is metabolized by glutaminase-1 (GLS1) to form the gas NH₃. NH₃ stimulates the production of mitochondrial reactive oxygen species (ROS) which causes the activation and translocation of NF-E2-related factor-2 transcription factor (Nrf2) into the nucleus, where it binds to the antioxidant responsive element (ARE) in the promoter region of the gene to trigger HO-1 transcription. HO-1 catalyzes the conversion of heme to carbon monoxide (CO) and biliverdin, the latter being rapidly metabolized to bilirubin by biliverdin reductase (BR). CO and the bile pigments (biliverdin and bilirubin) promote vascular homeostasis by inhibiting apoptosis, oxidative stress, inflammation, arterial tone, and vascular smooth muscle cell (SMC) proliferation and migration.

Figure 3

Emerging role of l-glutamine (Gln) in cardiovascular health and disease. Multiple mechanisms mediate the beneficial actions of Gln. In particular, Gln exerts potent antioxidant, anti-inflammatory, and anti-apoptotic effects in the circulation by stimulating the expression of glutathione, heat shock proteins, and heme oxygenase-1. In addition, l-glutamine stimulates blood flow and fluidity by generating nitric oxide. Moreover, Gln alleviates many known risk factors for cardiovascular disease, including dyslipidemia, glucose intolerance, insulin resistance, hypertension, and obesity. However, in some instances, excessive shunting of l-glutamine into the Krebs cycle can promote cardiovascular disease by stimulating aberrant vascular cell proliferation, migration, and collagen synthesis.