Glycine’s Role in Cardiovascular Health and Associated Disorders

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The growing prevalence of cardiovascular diseases (CVDs) and their associated risk factors, such as type 2 diabetes and nonalcoholic fatty liver disease (NAFLD), underscores the importance of understanding the biochemical agents that can mitigate these conditions. One such agent is glycine, the simplest proteinogenic amino acid with a unique hydrogen atom as its side chain, making it the only achiral amino acid. Glycine’s multifaceted role in human metabolism and its potential therapeutic benefits for cardiovascular health make it a crucial subject of study.

Glycine and its Metabolic Pathways

Glycine, an alpha-amino acid belonging to the serine family, is synthesized in the human body from sources such as glyoxylate, glucose (via serine), betaine, and likely threonine, as well as during the endogenous synthesis of L-carnitine. Despite the body’s ability to synthesize glycine, several animal models have suggested that glycine may be conditionally essential, requiring a dietary intake of approximately 1.5–3 g/day to maintain a physiological plasma concentration ranging from 200 to 300 µmol/L.

The synthesis of glycine is vital for producing biomolecules like creatine and purine nucleotides, contributing to its therapeutic potential. Studies have demonstrated glycine’s anti-inflammatory properties, enhancement of insulin response, and stimulation of glutathione biosynthesis, which is essential for antioxidant protection in all tissues. Furthermore, glycine’s role in reinforcing the extracellular matrix and its effectiveness against viral infections highlight its significance in maintaining overall health.

Glycine and Cardiovascular Health

The beneficial effects of glycine on cardiovascular health are attributed to its involvement in several biochemical pathways. Glycine’s cytoprotective benefits, achieved without harmful side effects, are particularly noteworthy. The plasma concentration of glycine has been shown to impact the severity of schizophrenia symptoms, and low levels are often observed in children with autism compared to control groups.

Glycine Levels and Acute Myocardial Infarction

Acute myocardial infarction (AMI) is a critical condition resulting from the acute obstruction of a coronary artery, leading to the necrosis of heart muscle tissue. Symptoms include chest discomfort, nausea, and sweating, which are diagnosable through electrocardiography (ECG) and serologic markers. In the United States, approximately 1 million myocardial infarctions occur each year.

A study by Ding et al. involving 4,109 participants undergoing coronary angiography for suspected stable angina pectoris found that plasma glycine levels were inversely associated with the risk of AMI. Women generally had higher plasma glycine levels than men, correlating with a favorable lipid profile and a lower prevalence of obesity, hypertension, and diabetes mellitus. This relationship highlights the role of glycine-dependent reactions in lipid metabolism and cholesterol transport, specifically through the catabolism of excess S-adenosylmethionine via the enzyme glycine-N-methyltransferase (GNMT) and its remethylation into sarcosine.

Additionally, research by Li et al. demonstrated that glycine could reduce myocardial fibrosis in rats following myocardial infarction by modulating the signal transducer and activator of the transcription 3/Nuclear Factor-κB/transforming growth factor-β axis. In another study by Zhong et al., glycine administered intraperitoneally to rats reduced myocardial ischemia-reperfusion injury by inhibiting myocardial apoptosis and suppressing phosphorylated p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase.

Glycine and Aortic Conditions

The aorta, responsible for transporting oxygen-rich blood throughout the body, is prone to various disorders, including aortic aneurysms, aortic arch syndrome, aortic insufficiency, and others. On average, an estimated 200 million liters of blood are transported through the aorta over a lifetime.

Wang et al. conducted a study on 33 human subjects, including those with coronary heart disease (CHD) without aortic lesions, acute aortic dissection (AD), and chronic AD. Using liquid chromatography and mass spectrometry (LC-MS/MS), the researchers identified significant differences in amino acid profiles, including glycine, between acute AD patients and CHD patients. These findings suggest that the amino acid profile could serve as a biomarker for AD, providing a novel and non-invasive diagnostic method.

Chao de la Barca et al. used a targeted metabolomics approach on an experimental aortic aneurysm model in Ldlr−/− mice, revealing significant hyperlipidemia and altered amino acid concentrations. The study found decreased levels of glutamine, glycine, taurine, and carnitine, and increased levels of branched amino acids (BCAA), suggesting that glycine-based therapies could mitigate atherosclerosis through antioxidant effects mediated by the induction of glutathione biosynthesis.

Furthermore, Yin et al. found that a glycine-rich diet could reduce the histopathological changes associated with chronic rejection in aortic allograft transplants. Glycine’s protective ability against hypoxia-reoxygenation injury in the liver and its immunosuppressive properties suggest potential therapeutic applications for aortic conditions.

Glycine’s Role in Angiogenesis and Tumor Inhibition

Angiogenesis, the natural process of forming new blood vessels, is regulated by chemical signals in the body, such as the vascular endothelial growth factor (VEGF). Glycine’s role in angiogenesis varies based on dosage, with low doses promoting angiogenesis and high doses exhibiting anti-angiogenic effects.

Tsuji-Tamura et al. explored the PI3K/Akt/mTOR signaling pathway and its interaction with glycine, finding that low glycine concentrations positively affected vascular elongation in transgenic zebrafish embryos, while high concentrations reduced vascular development. Chen et al. also found that glycine could reduce cerebrovascular remodeling in rats after a stroke by targeting glycine receptor alpha 2 and vascular endothelial growth factor receptor 2.

Glycine’s potential benefits for ischemic conditions, such as atherosclerosis, include aiding therapeutic angiogenesis, restoring blood flow, and rescuing ischemic tissue. Gou et al. demonstrated that glycine transporter 1 (GlyT1) activation by endothelial growth factor led to increased intracellular glycine, inhibiting the opening of the voltage-dependent anion channel 1 on the mitochondrial outer membrane.

Some studies suggest that dietary glycine can inhibit tumor growth by reducing serum-induced proliferation and migration of endothelial cells and dampening VEGF-A-mediated angiogenic signaling in human hepatocellular carcinoma.

Dietary Glycine Supplementation for Endothelial Dysfunction

Endothelial dysfunction, a non-obstructive coronary artery disease, involves the constriction of large blood vessels on the heart’s surface. Brawley et al. found that dietary glycine repletion could reverse endothelial dysfunction in protein-restricted pregnant rat dams, suggesting that glycine supplementation could protect the fetus from abnormal cardiovascular programming.

Gómez-Zamudio et al. demonstrated that oral glycine treatment improved vascular endothelial function in aged rats by enhancing eNOS expression and reducing the role of superoxide anion and contractile prostanoids, which increase nitric oxide bioavailability.

Effects of Glycine on Pathologic Cardiac Hypertrophy

Cardiac hypertrophy, characterized by the thickening of the heart muscle, is an adaptive response to hemodynamic stress. Lu et al. found that pre-treatment with glycine significantly attenuated murine cardiac hypertrophy induced by transverse aortic constriction or angiotensin II administration. Glycine’s antagonistic effect on the Ang II stimulated release of transforming growth factor β and endothelin-1 by cardiomyocytes highlights its potential as a cardioprotector against pressure overload-induced cardiac hypertrophy.

Glycine and Low Peritoneal Vasoreactivity to Dialysis Solutions

Chronic renal failure (CRF) often requires dialysis to remove waste and excess water from the blood. Zakaria and Kandi’s study on the peritoneal dialysis solution (PDS)-mediated vasoreactivity in rats found that glycine supplementation restored vasoreactivity in elderly rats, suggesting its potential for improving peritoneal vasoreactivity in older adults undergoing dialysis.

Correlation between Glycine, Insulin Resistance, and Other Cardio-Metabolic Diseases

Insulin resistance (IR) affects glucose uptake in tissues sensitive to insulin, leading to cardio-metabolic disorders, including obesity, dyslipidemia, and hypertension. Wittemans et al. found that glycine is genetically associated with lower coronary heart disease (CHD) risk, partly driven by blood pressure. Do Prado et al. also identified a correlation between circulating glycine levels and cardiovascular disease biomarkers in children with obesity.

Research on sucrose-fed rats demonstrated that glycine intake reduced plasma-free fatty acids, adipose cell size, and blood pressure. Additionally, glycine has shown potential in combating dietary fructose by activating glycine-gated chloride channels and improving symptoms of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

Supplementing with glycine and N-acetylcysteine has been shown to improve glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, aging hallmarks, metabolic defects, muscle strength, cognitive decline, and body composition. Kumar et al. found that glycine/N-acetylcysteine supplementation improved these parameters in older adults, suggesting its potential for enhancing overall health and longevity.

Conclusion

Glycine’s multifaceted role in human metabolism and its therapeutic potential for cardiovascular health make it a crucial subject of study. Its involvement in lipid metabolism, cholesterol transport, and anti-inflammatory and antioxidant pathways highlights its significance in mitigating cardiovascular diseases and associated disorders. Further research on glycine’s biochemical mechanisms and therapeutic applications could lead to new strategies for preventing and treating cardiovascular conditions, improving overall health outcomes.


reference link : https://www.mdpi.com/2813-2475/3/2/16

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