Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective

Abstract

Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.

Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway

“…In the sample set investigated, ARG1 was substantially while ARG2 borderline significantly downregulated in tumors. Consistent with counter-regulatory mechanisms in the ARG/NOS interplay [ 44 ], NOS2 was markedly upregulated and ARG1 tended to positively correlate with the systemic concentration of ADMA, a NOS inhibitor. Moreover, NOS2 was the only pathway enzyme clearly expressed at a higher level in metastasizing tumors.…”

“…Arginases compete with NOS enzymes for arginine and, as NOS activity is considered cancer-promoting, strategies based on upregulating endogenous arginase activity or introduction of exogenous arginine-consuming enzymes are currently being tested [ 11 , 12 ]. Moreover, arginases synthesize ornithine and, therefore, supply substrates for polyamine biosynthesis [ 44 ]. Accordingly, ARG2 expression level, and in tumors also that of ARG1 , was positively correlated with ODC1 , a key regulatory enzyme of the pathway.…”

“…Moreover, NOS2 was the only pathway enzyme clearly expressed at a higher level in metastasizing tumors. In line with its proinflammatory character, NOS2 expression correlated positively with circulating immune and inflammatory mediators, whilst ARG1 , a hepatocyte isoform [ 44 ], correlated with HGF, positively in tumors but negatively in adjacent tissue. Consistent with this observation, HGF/c-met signaling axis was shown to induce macrophage M2 polarization as its inhibition upregulated NOS2 and other M1 polarization markers and downregulated ARG1 [ 48 ].…”

Protection against Doxorubicin‐Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6

“…Both two arginase isoforms, including arginases 1 and 2, are involved in the NO production in various cardiovascular diseases such as atherosclerosis and myocardial ischemia-reperfusion injury [ 23 , 24 ]. Arginase 2 (ARG 2) is the predominant isoform expressed in cardiac tissue [ 25 , 26 ]. However, the role of ARG 2 has not been reported in cardiomyocytes and further study is needed.…”

Study the Sensitivity and Specificity of Urinary Arginase in Bladder Cancer Patients in Babylon Governorate

“…Arginase is a manganese metalloenzyme that hydrolyses L-arginine to urea and L-ornithine. Arginase exists in two distinct isoforms, arginase I and II, that share 60% sequence homology [11] . Although both isoforms are found throughout the body, arginase I is a cytosolic enzyme mainly localized in the liver [12] .…”