Metabolism of asymmetric dimethylarginine in hypoxia: from bench to bedside

Abstract

Acute hypoxia and chronic hypoxia induce pulmonary vasoconstriction. While hypoxic pulmonary vasoconstriction is a physiological response if parts of the lung are affected, global exposure to hypoxic conditions may lead to clinical conditions like high-altitude pulmonary hypertension. Nitric oxide is the major vasodilator released from the vascular endothelium. Nitric oxide-dependent vasodilation is impaired in hypoxic conditions. Inhibition of nitric oxide synthesis is the most rapid and easily reversible molecular mechanism to regulate nitric oxide-dependent vascular function in response to physiological and pathophysiological stimuli. Asymmetric dimethylarginine is an endogenous, competitive inhibitor of nitric oxide synthase and a risk marker for major cardiovascular events and mortality. Elevated asymmetric dimethylarginine has been observed in animal models of hypoxia as well as in human cohorts under chronic and chronic intermittent hypoxia at high altitude. In lowlanders, asymmetric dimethylarginine is high in patients with pulmonary hypertension. We have recently shown that high asymmetric dimethylarginine at sea level is a predictor for high-altitude pulmonary hypertension. Asymmetric dimethylarginine is a highly regulated molecule, both by its biosynthesis and metabolism. Methylation of L-arginine by protein arginine methyltransferases was shown to be increased in hypoxia. Furthermore, the metabolism of asymmetric dimethylarginine by dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) is decreased in animal models of hypoxia. Whether these changes are caused by transcriptional or posttranslational modifications remains to be elucidated. Current data suggest a major role of asymmetric dimethylarginine in regulating pulmonary arterial nitric oxide production in hypoxia. Further studies are needed to decipher the molecular mechanisms regulating asymmetric dimethylarginine in hypoxia and to understand their clinical significance.

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients

“…ADMA is an endogenous, competitive inhibitor of NO synthesis an—like its congener molecule, SDMA—an inhibitor of cellular L-arginine uptake 18 . Both dimethylarginines are formed through the action of protein arginine methyltransferases (PRMTs), enzymes that are involved in innate immune responses and in the response to hypoxia in the lung 19 . PRMTs produce mainly SDMA in the central nervous system, but ADMA in many other organs including heart, circulatory system, and lungs (for review, cf.…”

“…NO synthesis is tightly regulated 17 . Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are endogenous modulators of NO synthesis and intracellular L-arginine availability in the endothelium 18 ; their circulating concentrations being dysregulated in hypoxia 19 . In addition, inhibition of NO synthesis by ADMA and SDMA may affect immune response and inflammatory reaction, as they also interfere with inducible NO synthase, an enzyme that is upregulated by inflammatory cytokines 20 .…”

Endothelial Dysfunction Driven by Hypoxia—The Influence of Oxygen Deficiency on NO Bioavailability

“…Second, hypoxia can affect DDAH activity and ADMA metabolism. ADMA has been shown to accumulate in animal hypoxia models, as well as in human studies [152]. Higher ADMA but lower L-Arg serum levels were observed in patients with obstructive sleep apnea syndrome, in relation to healthy controls [153] and in patients with pulmonary hypertension [154].…”

An Overview of Vascular Dysfunction and Determinants: The Case of Children of African Ancestry

“…Dimethyl arginines are formed during the methylation of L-arginine residues within specific proteins, a process that is catalyzed by arginine methyltransferase. ADMA is released following a cleavage of methylated proteins during physiological protein turnover (47). Under physiological conditions, ADMA is excreted in urine.…”