Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling

Zhu, Chengwei; Yu, Yi; Montani, Jean‐Pierre; Ming, Xiu‐Fen; Yang, Zhihong

doi:10.1186/s13104-017-2399-x

Cited by 39 publications

(38 citation statements)

References 34 publications

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“…Intriguingly, NO production is reportedly decreased in senescent endothelial cells (109,110). Reciprocally, NO activates telomerase (111) to prevent endothelial cell senescence, thereby decreasing presentation of the proatherogenic, leukocyte-binding receptors VCAM1 and ICAM1 (112). Similarly, NO production may inhibit VSMC senescence.…”

Section: Senescent Cells Drive Age-related Cardiovascular Diseasesmentioning

confidence: 99%

Senescent cells: a therapeutic target for cardiovascular disease

Childs¹,

Hu²,

Deursen³

2018

Journal of Clinical Investigation

151

122

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Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.

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Section: Senescent Cells Drive Age-related Cardiovascular Diseasesmentioning

confidence: 99%

Senescent cells: a therapeutic target for cardiovascular disease

Childs¹,

Hu²,

Deursen³

2018

Journal of Clinical Investigation

151

122

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“…Reported molecular mechanisms underlying the Arg1mediated T cell suppression are the downregulation of CD3z (34) and the induction of cell cycle arrest that was characterized by a failure to upregulate cyclin D2 and D3 (35,36), a decline of mTORC1 activity, and a repression of lipid biosynthesis-linked genes (36). Third, Arg1 was also found to deprive endothelial or type 3 NO synthase (NOS3) of L-arginine, which resulted in enhanced immune cell adhesion to vascular endothelium due to the lack of antiadhesive endothelial NO (37,38). In addition to these immunoregulatory effects, Arg1 expressed by myeloid and endothelial cells has been implicated in promoting wound healing and facilitating tissue repair (33,39) because its product ornithine is a precursor of polyamines and proline, which are required for cell proliferation and collagen synthesis, respectively (1).…”

mentioning

confidence: 99%

Resolution of Cutaneous Leishmaniasis and Persistence ofLeishmania majorin the Absence of Arginase 1

Paduch

Debus

Rai

et al. 2019

The Journal of Immunology

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Arginase (Arg) 1 is expressed by hematopoietic (e.g., macrophages) and nonhematopoietic cells (e.g., endothelial cells) and converts L-arginine into ornithine and urea. The enzyme is implicated in tissue repair but also antagonizes the production of NO by type 2 NO synthase in myeloid cells and thereby impedes the control of intracellular parasites such as Leishmania major. In this study, we tested whether Arg1 is required for spontaneous healing of acute cutaneous leishmaniasis in C57BL/6 mice and for lifelong parasite persistence in draining lymph nodes (dLNs) of healed mice. In vitro, bone marrow-derived macrophages and lymphoid endothelial cells readily expressed Arg1 in response to IL-4 and/or IL-13, whereas skin or dLN fibroblasts failed to do so, even during hypoxia. In vivo, Arg1 was found in skin lesions and, to a much lower extent, also in dLNs of acutely infected C57BL/6 mice but became undetectable at both sites after healing. Deletion of Arg1 in hematopoietic and endothelial cells using Tie2Cre +/2 Arg1 fl/fl C57BL/6 mice abolished the expression of Arg1 in skin lesions and dLNs but did not affect development and resolution of skin lesions, parasite burden, NO production, or host cell tropism of L. major during the acute or persistent phase of infection. Similar to wild-type controls, parasites persisting in Arg1-deficient mice favored NO synthase 22negative areas and mainly resided in myeloid cells and fibroblasts. We conclude that Arg1 expression by hematopoietic and endothelial cells is completely dispensable for clinical resolution of cutaneous leishmaniasis and for long-term persistence of L.

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“…Recently, Arginase gained interest as a potential target to improve NO production [64,65]. In a study on non-senescent human endothelial cells, overexpression of Arg-I led to eNOS-uncoupling, expression of senescence markers and inflammatory markers as well as monocyte adhesion to endothelial cells via increased oxidative stress [66]. In line with this, oxidative stress in older animals was associated with elevates Arginase 1 and eNOS uncoupling [67].…”

Section: Arginase Inhibitionmentioning

confidence: 79%

Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis

Gori¹

2020

IJMS

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Amyl nitrite was introduced in 1867 as the first molecule of a new class of agents for the treatment of angina pectoris. In the following 150 years, the nitric oxide pathway has been the subject of a number of pharmacological approaches, particularly since when this elusive mediator was identified as one of the most important modulators of vascular homeostasis beyond vasomotion, including platelet function, inflammation, and atherogenesis. While having potent antianginal and antiischemic properties, however, nitric oxide donors are also not devoid of side effects, including the induction of tolerance, and, as shown in the last decade, of oxidative stress and endothelial dysfunction. In turn, endothelial dysfunction is itself felt to be involved in all stages of atherogenesis, from the development of fatty streaks to plaque rupture and thrombosis. In the present review, we summarize the agents that act on the nitric oxide pathway, with a particular focus on their potentially beneficial antiatherosclerotic and unwanted pro-atherosclerotic effects.

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Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling

Cited by 39 publications

References 34 publications

Senescent cells: a therapeutic target for cardiovascular disease

Senescent cells: a therapeutic target for cardiovascular disease

Resolution of Cutaneous Leishmaniasis and Persistence ofLeishmania majorin the Absence of Arginase 1

Exogenous NO Therapy for the Treatment and Prevention of Atherosclerosis

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