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  • Enhanced arginase activity and the resultant decreases in L

    2024-02-05

    Enhanced arginase activity and the resultant decreases in L-arginine levels can also impair T cell mediated immune function and allow tumor growth by limiting the supply of L-arginine needed for the formation of cytotoxic levels of NO by iNOS [10]. Increased arginase expression/activity may also limit iNOS expression through reducing L-arginine required for iNOS translation [11]. L-arginine is also the substrate for nitric oxide synthase (NOS) (Box 2, Figure 2). When arginase activity is excessive, it can compete with NOS for their common substrate, L-arginine. When the supply of L-arginine required for NO production is insufficient, NOS will become uncoupled 12, 13 and will produce less NO and use more molecular oxygen to form superoxide. The superoxide will react rapidly with any available NO to form peroxynitrite, further decreasing NO and further uncoupling NOS by oxidizing the cofactor BH4[14] (Figure 3).
    Arginase in cardiovascular disease In the time since NO was named ‘The Molecule of the Year’ in Science[15], many cardiovascular disease states have been linked to impaired vascular endothelial cell production of NO. In addition, reduced availability of L-arginine has been implicated in vascular dysfunctions. Realization that enhanced arginase activity might compete with NOS for L-arginine and reduce NO levels fueled several studies on its involvement in states of vascular endothelial dysfunction. Elevated levels of L-ornithine, the product of arginase, also have been shown to be a key factor in vascular smooth muscle hyperplasia, fibrosis, and stiffening. We review below some of the recent evidence for the involvement of these arginase pathways in cardiovascular disease and injury conditions.
    Arginase and CNS disease/injury Arginase function in increasing polyamine formation is known to have a positive role in neuroprotection and neural regeneration 61, 62. However, upregulation of arginase has also been linked to CNS disease conditions, including stroke, Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, traumatic PRL-3 Inhibitor injury, and several retinal diseases. Immunolocalization studies have shown the presence of both A1 and A2 in brain, especially in hippocampal neurons [63]. Both isoforms are also expressed in retina. Prominent immunoreactivity for A1 is evident in retinal glia 64, 65, and A2 is abundant in horizontal cells, photoreceptor inner segments, and cellular processes throughout the neural retina, consistent with its mitochondrial localization 66, 67. NO release is a crucial component of neurovascular signaling pathways and is particularly important for maintaining cerebral blood flow (CBF). Disruption of NO pathways is a key feature of brain injury. NO derived from eNOS, nNOS, and iNOS has been shown to influence the evolution of brain damage in different ways [68]. Uncontrolled NO production through iNOS during inflammation, or NO formed by nNOS, promote nitrative stress, leading to neurodegeneration and apoptosis. However, NO from eNOS maintains blood flow and limits platelet aggregation and leukocyte attachment to the vessel wall, thereby dampening oxidative stress and inflammation. By contrast, arginase can be both a target and source of oxidative stress and inflammation. Expression of A1 has been shown to be increased by oxidative stress and inflammatory mediators 8, 35, 36, and overactive arginase can contribute to further increases in oxidative stress and inflammation by causing NOS uncoupling. The role of arginase activity in inflammation, oxidative stress, and CNS injury has been considered only recently. We explore the current evidence for involvement of the arginase pathways in neurovascular injury in the sections that follow.
    Arginase inhibitors The first arginase inhibitors to be developed had non-specific actions and many side effects because of the high concentrations required [8]. For example, norvaline is a substrate for amidotransferases [88]. Similarly, while L-NOHA is a potent inhibitor for arginase, it is also an intermediate precursor in the production NO from L-arginine by NOS. An analog, nor-NOHA is also a potent arginase inhibitor, but has a much longer half-life than NOHA. Neither inhibits NOS. α-Difluoromethylornithine (DFMO) is a non-specific weak inhibitor of arginase, but is a potent inhibitor of ornithine decarboxylase [8]. Thus, the effects of DFMO in increasing NO production in models of elevated arginase activity are likely due to increased accumulation of ornithine which is known to inhibit arginase [89]. Besides producing urea, arginase is also involved in synthesis of polyamines and amino acids such as ornithine, proline, and glutamate. In fact, ornithine, leucine, valine, lysine, isoleucine, and nor-valine inhibit arginase, with ornithine being the most potent [90]. Furthermore, L-citrulline is an allosteric inhibitor of arginase [91], but it also increases NO formation.