Asymmetric dimethylarginine (ADMA)

Asymmetric dimethylarginine (ADMA) is an organic metabolic byproduct of protein modification, generated from the methylation of protein arginine residues by protein arginine methyltransferases. It is a naturally occurring analogue of L-arginine and is found in the bloodstream. Due to its similar structure to L-arginine, ADMA competitively inhibits the production of nitric oxide, a molecule critical for endothelial cell function, from L-arginine by nitric oxide synthase. As such, ADMA is toxic to endothelial cells. Endothelial cells modulate vascular tone by synthesizing and releasing a variety of factors that drive blood vessel formation, regulate coagulation and fibrinolysis, aid inflammatory reactions, and more. The detrimental impact ADMA has on endothelial cell function has led many researchers to investigate how ADMA contributes to various disease.

Notably, ADMA is an important biomarker and risk factor for cardiovascular disease, and most research on ADMA has focused on this association. However, high levels of ADMA are also associated with smoking, hypertension, liver failure, diabetes mellitus, preeclampsia, and other conditions. Drugs used to treat diabetes mellitus, coronary artery disease, osteoporosis, peripheral arterial occlusive disease, and others, can lower plasma ADMA levels.

ADMA in cardiovascular diseases

ADMA inhibits nitric oxide synthesis by blocking the conversion of L-arginine to nitric oxide, a chemical important for endothelial function and cardiovascular health¹. High plasma and low urinary ADMA concentrations are considered cardiovascular risk factors and have emerged as predictors of cardiovascular events and death for a range of diseases in adults². Since ADMA interferes with the production of nitric oxide, a potent vasodilator made by nitric oxide synthase, elevated levels in the circulation can restrict blood flow³. Furthermore, elevated ADMA concentrations can lead to reduced arterial smooth muscle contraction as well as endothelial adhesiveness. Thus, ADMA interferes with endothelial function, increasing the risk for major adverse cardiovascular events and cardiovascular disease. Additionally, ADMA-induced cholesterol efflux causes endothelial dysfunction, which can lead to cholesterol accumulation in blood vessels and cause atherosclerosis.

ADMA is eliminated from the body by a combination of renal excretion and catabolism by dimethylarginine dimethylaminohydrolase (DDAH). As such, renal failure increases the risk of ADMA-mediated cardiovascular events and disease. These risks are further compounded by hypercholesterolemia, hypertension, smoking, diabetes mellitus, homocysteine, and vascular disease. To corroborate the association of ADMA and cardiovascular disorders, a few studies have directly examined the role of ADMA in patients. When researchers administered ADMA to patients, they displayed increased coronary artery blood pressure and systemic vascular resistance. Additionally, ADMA administration reduced cardiac output and heart rate during exercise⁴.

Patients with congenital and coronary heart disease and pulmonary hypertension display high plasma ADMA concentrations, and these levels could contribute to disease pathogenesis by restricting blood flow. Supporting this hypothesis, one study found that ADMA levels were positively correlated with artery thickness5. Thickening in this study was likely caused by ADMA-induced arterial plaque buildup.

ADMA in pulmonary diseases

Recent studies suggest that ADMA may play a role in the progression of pulmonary diseases, such as idiopathic pulmonary fibrosis. One study showed that animals treated with ADMA developed increased lung collagen deposition, a feature of experimental lung fibrosis6. ADMA-collagen deposition can lead to inflammatory cell infiltration as well as fibrosis. In humans, preterm infants that required mechanical ventilation to oxygenate their lungs showed increased ADMA plasma levels. This indicates that ADMA may hamper lung function early in life.

In adults, multiple studies have reported conflicting results on the impact of cigarette smoke on ADMA. Patients with chronic obstructive pulmonary disease (COPD) generally exhibit higher levels of circulatory ADMA compared to healthy individuals, though contradictory reports exist. Furthermore, some studies have reported that plasma ADMA levels positively correlated with COPD disease severity and mortality⁷. Some researchers have suggested that therapeutic modification of the L-arginine-nitric oxide pathway using L-arginine or recombinant DDAH supplementation may be able to improve COPD patient outcomes. However, more mechanistic studies are needed to elucidate the role of ADMA in lung function and disease.

ADMA and autoimmunity

Multiple studies have suggested that ADMA contributes to the pathogenesis of both rheumatoid arthritis and osteoarthritis because elevated levels can suppress bone formation and promote inflammatory cytokine expression. Indeed, osteoarthritis and rheumatoid arthritis patients display elevated ADMA levels in the synovial fluid and circulation, respectively. One study showed that ADMA triggers cartilage destruction and chondrocyte senescence during osteoarthritis. The identification of elevated levels of ADMA in synovial fluid could help in the diagnoses of osteoarthritis⁸.

ADMA has also been implicated in multiple sclerosis, a chronic autoimmune condition of the central nervous system. Patients with multiple sclerosis have elevated ADMA concentrations in circulation. Using a mouse model, one study revealed that ADMA exacerbated MS-like disease and disrupted the blood brain barrier. Furthermore, the researchers showed that ADMA can promote pathogenic responses in immune cells⁹. Further research is needed to examine the role of ADMA in other autoimmune diseases.

ADMA and infection

ADMA induces microvascular inflammation, endothelial dysfunction, oxidative stress, and mitochondrial dysfunction. Patients with sepsis typically display high levels of ADMA, and plasma levels are correlated with mortality. A few studies have explored the role of ADMA in sepsis but have yielded conflicting results. Multiple preclinical studies have demonstrated that lowering ADMA levels, by increasing expression of the enzyme that breaks down ADMA, can improve septic patient outcomes¹⁰. By reducing ADMA, thus promoting endothelial nitric oxide synthase activity, nitric oxide becomes available to act as an anti-microbial in the blood and limit infection¹¹. However, additional studies are needed to confirm these findings in patients.

A recent study showed that serum levels of ADMA at the time of hospitalization are correlated with COVID-19 disease severity and the need for mechanical ventilation. Therapeutic approaches such as inhaled nitric oxide administration for patients with high levels of ADMA may be a valid strategy to treat COVID-19 disease; however, early studies have produced conflicting reports. Future studies using cell and animal models are needed to reveal the molecular mechanisms that underlie the regulation of ADMA during COVID-19¹².

ADMA and research

As of March 2024, there are almost 700 citations for ADMA in research publications (excluding books and documents) on Pubmed. The large number of publications linking ADMA to a broad range of physiological disorders suggests that any research seeking to better understand its role in pulmonary, infection, cardiovascular, autoimmune, and other settings may benefit from more mechanistic studies. Furthermore, given the number of diseases associated with high levels of ADMA, novel strategies that modulate ADMA levels may lead to targeted therapeutics for a number of diseases.

References

1. National Library of Medicine, National Center for Biotechnology Information. PubChem Compound Summary, N,N-dimethylarginine (CID 743123831). https://pubchem.ncbi.nlm.nih.gov/compound/123831
2. Schnabel R, Blankenberg S, Lubos E, et al. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res. 2005;97(5). doi:10.1161/01.RES.0000181286.44222.61
3. Leone A, Moncada S, Vallance P, et al. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339(8793):572-575. doi:10.1016/0140-6736(92)90865-Z
4. Achan V, Broadhead M, Malaki M, et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscle Thromb Vasc Biol. 2003;23(8):1455-1459. doi:10.1161/01.ATV.0000081742.92006.59
5. Zoccali C, Benedetto FA, Maas R, et al. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol. 2002;13(2):490-496. doi:10.1681/ASN.V132490
6. Wells SM, Buford MC, Migliaccio CT, et al. Elevated Asymmetric Dimethylarginine Alters Lung Function and Induces Collagen Deposition in Mice. Am J Respir Cell Mol Biol. 2009;40(2):179. doi:10.1165/RCMB.2008-0148OC
7. Vögeli A, Ottiger M, Meier MA, et al. Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Lung. 2017;195(6):717-727. doi:10.1007/S00408-017-0047-9
8. Wu Y, Shen S, Chen J, et al. Metabolite asymmetric dimethylarginine (ADMA) functions as a destabilization enhancer of SOX9 mediated by DDAH1 in osteoarthritis. Sci Adv. 2023;9(6). doi:10.1126/SCIADV.ADE5584
9. Singh I, Kim J, Saxena N, et al. Vascular and immunopathological role of Asymmetric Dimethylarginine (ADMA) in Experimental Autoimmune Encephalomyelitis. Immunology. 2021;164(3):602-616. doi:10.1111/IMM.13396
10. Mortensen KM, Itenov TS, Hansen MB, et al. Mortality in critical illness: The impact of asymmetric dimethylarginine on survival-A systematic review and meta-analysis. Acta Anaesthesiol Scand. 2019;63(6):708-719. doi:10.1111/AAS.13339
11. Aggarwal S, Gross CM, Kumar S, et al. Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury. Am J Respir Cell Mol Biol. 2014;50(3):614-625. doi:10.1165/RCMB.2013-0193OC
12. Sozio E, Hannemann J, Fabris M, et al. The role of asymmetric dimethylarginine (ADMA) in COVID-19: association with respiratory failure and predictive role for outcome. Sci Rep. 2023;13(1):1-10. doi:10.1038/s41598-023-36954-z