The prognostic biomarker L-homoarginine is a substrate of the cationic amino acid transporters CAT1, CAT2A and CAT2B

Abstract

Low plasma concentration of L-homoarginine is an independent predictor of cardiovascular events and total mortality. Experimental data indicate that supplementation of L-homoarginine may have protective effects. We aimed to elucidate the mechanisms involved in the cellular uptake of L-homoarginine, which are little understood, so far. Using human embryonic kidney (HEK293) cell lines stably overexpressing the human cationic amino acid transporters CAT1 [solute carrier family 7 (SLC7A1)], CAT2A (SLC7A2A) or CAT2B (SLC7A2B) we assessed the transport kinetics of L-homoarginine and interactions with the CAT substrates L-arginine and asymmetric dimethylarginine (ADMA). Significant uptake of L-homoarginine was observed for all three CATs with apparent KM-values of 175 ± 7 µM for CAT1 and 523 ± 35 µM for CAT2B. Saturation of CAT2A-mediated L-homoarginine uptake could not be reached. Uptake of L-homoarginine by any of the three CATs could be inhibited by L-arginine and ADMA. Significant inhibition of CAT1-mediated uptake of L-homoarginine by L-arginine already occurred in the physiological concentration range. Taken together these data demonstrate that L-homoarginine is a substrate of CAT1, CAT2A and CAT2B and that CAT1 is a key site with regard to physiological relevance and interactions with related substrates such as L-arginine.

Vectorial transport of the arginine derivatives asymmetric dimethylarginine (ADMA) and l-homoarginine by OATP4C1 and P-glycoprotein studied in double-transfected MDCK cells

“…So far, l -homoarginine has been characterized as substrate for the SLC7 family members CAT1, CAT2A and CAT2B with CAT1 being expressed in proximal tubule cells. For l -homoarginine, a K m value of 175 µM has been calculated for CAT1-mediated uptake (Chafai et al 2017 ). In addition, l -homoarginine is also a substrate of the SLC21/SLCO family member OATP4C1 located in the same membrane domain with a K m value of 49.9 µM (Taghikhani et al 2019 ).…”

“…ADMA has been characterized as low affinity substrate for CAT1 (Strobel et al 2012 ) and OCT2 (Strobel et al 2013 ). l -Homoarginine is also a substrate for CAT1 (Chafai et al 2017 ).…”

Homoarginine and inhibition of human arginase activity: kinetic characterization and biological relevance

“…For example HOMOARG is reported to be an alternative substrate for the enzyme NOS 20 , 35 , and despite its low affinity for the enzyme, it can directly increase NO availability 1 . Likewise, HOMOARG is a substrate of the different members of the cationic amino acid transporter (CAT) family of transporters and significantly inhibits the uptake of ARG by CAT-1, thus increasing ARG availability for NOS 36 . Furthermore, it may reduce blood pressure by facilitating the excretion of nitrate 1 , 37 .…”

Tackling endothelium remodeling in cardiovascular disease

“…Accumulating arginine is further catalyzed by protein arginine methyltransferases (PRMTs) encoded in mammalian genomes, resulting in three types of arginine methylation implicated in signal transduction and gene transcription. 51 In addition, it is known L-homoarginine inhibits the alkaline phosphatase implicated in vascular calcification. 22 Increased L-homoarginine concentrations might exert a positive effect on endothelial function.…”

“…52,53 So, supplementation with L-homoarginine and L-arginine derivatives (and others selected pharmaceutical supplements), dietary beneficial habits, intake of antioxidant and anti-inflammatory foods and balanced physical activity improved endothelium function. 9,51 At a pathological environment, the endothelium assembly (arrangement of a proatherosclerotic structure) and function (deficit of guarding role) are altered, leading to endothelium dysfunction. Shortage of NO in the endothelium is caused by a severe decline of NO formation by eNOS.…”