Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Abstract

Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism

“…In contrast, knock-out of Ddah1 led to elevated levels of ADMA and decreased NO in tissues and plasma (Hu et al 2011 ; Zhao et al 2021 ). A pathophysiological role of DDAH1 via the ADMA/NO pathway has already been established in non-CNS conditions, including cardiovascular (Leiper et al 2007 ; Dayoub et al 2008 ; Hu et al 2011 ) and renal disease (Vallance et al 1992 ; Tomlinson et al 2015 ), angiogenesis, vascular permeability and wound healing (Smith et al 2003 ; Achan et al 2005 ; Jacobi et al 2005 ; Konishi et al 2007 ; Wang et al 2021 ), vascular remodeling (Rodionov et al 2010 , 2022 ; Kopaliani et al 2021 ) and insulin sensitivity (Sydow et al 2008 ); however, its implication in the CNS is not yet extensively studied. So far, studies have shown that DDAH1 is widely expressed in the postnatal CNS, specifically in neurons, astrocytes and the endothelial cells of blood vessels (Tran et al 2000 ; Kozlova et al 2022 ), suggesting that DDAH1 may be a principal NO regulator in the brain.…”

Preliminary Study on the Pathogenic Mechanism of Jujube Flower Disease in Honeybees (Apis mellifera ligustica) Based on Midgut Transcriptomics

“…AGXT2 is a class III pyridoxal-phosphate-dependent mitochondrial aminotransferase that affects lipid metabolism by elevating or reducing other substrates of this enzyme [28,29]. Moreover, the overexpression of AGXT2 protects against asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling [30]. In this study, we found that AGXT2 expression was significantly lower in honeybees with jujube flower disease, suggesting that jujube flower disease not only affects the digestive system but also has an impact on the circulatory system of honeybees.…”

Interaction of asymmetric dimethylarginine, troponin I level, and diabetes mellitus 2 type severity in patients with acute myocardial infarction

“…ADMA is a metabolite of arginine, the determination of which is useful to evaluate cardiovascular disease, kidney disease, and nonalcoholic fatty liver disease 34 . The increased concentration of ADMA in the blood plasma is connected to the increased risk of mortality and unacceptable cerebrovascular diseases, as is especially evident in the case of AMI [35][36][37][38][39][40] . In AMI, the necrotic death of cardiomyocytes occurs, characterized by the rupturing of the sarcolemma in response to a critical level of energy depletion after more than 15 minutes of ischemia.…”