Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling

Xiong, Yuyan; Fru, Michael Forbiteh; Yu, Yi; Montani, Jean‐Pierre; Ming, Xiu‐Fen; Yang, Zhihong

doi:10.18632/aging.100663

Cited by 37 publications

(40 citation statements)

References 34 publications

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“…The DAF-FM fluorescence was observed under an inverted fluorescent microscope (EVOS). Five independent images for each well were analyzed using image analysis (ImageJ software, MD) according to previous reports [36, 37]. …”

Section: Methodsmentioning

confidence: 99%

Angiotensin-(1–7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways

Xiao

Zhang

et al. 2015

Experimental Cell Research

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Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways.

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Section: Methodsmentioning

confidence: 99%

Angiotensin-(1–7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways

Xiao

Zhang

et al. 2015

Experimental Cell Research

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“…However, L-arginine supplementation resulted in increased plasma arginine and ornithine levels without changing citrulline levels, suggesting that most of the arginine administered is metabolized by arginase rather than NOS. (9) Furthermore chronic L-arginine exposure has been demonstrated to increase endothelial cell arginase, essentially “adding fuel to the fire.” (10) …”

Section: Introductionmentioning

confidence: 99%

Arginase Inhibition Reverses Endothelial Dysfunction, Pulmonary Hypertension, and Vascular Stiffness in Transgenic Sickle Cell Mice

Steppan¹,

Tran²,

Bead³

et al. 2016

Anesthesia &Amp; Analgesia

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Background In sickle cell disease (SCD), hemolysis results in the release and activation of arginase, an enzyme that reciprocally regulates nitric oxide (NO) synthase activity and thus, NO production. However, simply supplementing the common substrate L-arginine fails to improve NO bioavailability. In this study, we tested the hypothesis that arginase inhibition would improve NO bioavailability and thereby attenuate systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. Methods and Results We studied 5 month-old transgenic sickle cell (SC) mice and age-matched wild-type (WT) controls. SC mice were treated with the arginase inhibitor, 2(S)-Amino-6-BoronoHexanoic acid (ABH; ~400 μg/d) for four weeks or left untreated. Vascular arginase activity was significantly higher at baseline in untreated SC mice compared to WT controls (SC vs. WT, 346 ±69.3 vs. 69 ±17.3 pmol urea/mg protein/minute; p=0.0043; n = 4–5 animals per group). ABH treatment may significantly decrease arginase activity to levels near WT controls (SC + ABH 125.2 ±17.3 pmol urea/mg protein/minute, p=0.0213). Aortic strips from untreated SC mice showed decreased nitric oxide (NO) and increased reactive oxygen species (ROS) production (NO: fluorescence rate 0.76 ±0.14 vs. 1.34 ±0.17 RFU/s, p = 0.0005 and ROS: fluorescence rate 3.96 ±1.70 vs. 1.63 ±1.20 RFU/s, p = 0.0039; n = 3–5 animals per group). SC animals treated with ABH for 4 weeks demonstrated NO (fluorescence rate: 1.16 ±0.16) and ROS (fluorescence rate: 2.02 ±0.45) levels comparable to age-matched WT controls (n = 3–5 animals per group). The maximal endothelial-dependent vasorelaxation response to acetylcholine was impaired in aortic rings from SC mice compared to WT (57.7 ±8.4% vs. 80.3 ±11.0%; p=0.02; n = 6 animals per group). The endothelial-independent response was not different between groups. In SC mice, the right ventricular cardiac output index, and end-systolic elastance were similar (4.60 ±0.51 vs 2.9 ±0.85 ml/min/100g and 0.89 ±0.48 vs 0.58 ±0.11 mmHg/μl), while the pulmonary vascular resistance index and right ventricular end systolic pressure were higher (2.9 ±0.28 vs 5.5 ±2.0 mmHg×min/μl/100g and 18.9 ±1.1 vs 23.1 ±4.0 mmHg; n = 8 animals per group). Pulse wave velocity (a measure of arterial stiffness) was higher in SC mice compared to WT (3.74 ±0.54 vs. 3.25 ±0.21 m/s; n = 20 animals per group), arginase inhibition for four weeks significantly reduced the vascular SC phenotype to one similar to WT animals (p=0.0009). Conclusion Arginase inhibition improves NO bioavailability and thereby attenuates systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. Therefore, arginase is a potential therapeutic target in the treatment of cardiovascular dysfunction in SCD.

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“…Positive effects are associated with blockade of the enzyme -arginase II. The potential effects of the blockade of this enzyme have been confirmed in many experiments (Xiong et al 2014;Sobolev et al 2018). It was fair to expect that the positive effects obtained in the correction of morphofunctional disorders of ADMA-like preeclampsia by other arginase II inhibitors would be found in the studied pharmacological agents Nguyen et al 2016;Severinova et al 2019).…”

Section: Resultsmentioning

confidence: 90%

Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia

Локтева¹,

Rozhkov²,

Гуреев³

et al. 2020

RRP

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Citation: Lokteva TI, Rozhkov IS, Gureev VV, Gureeva AV , Zatolokina MA, Avdeyeva EV, Zhilinkova LA, Prohoda EE, Yarceva EO (2020) Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia. Research Results in Pharmacology 6(1): 29-40. https:// Abstract Introduction: Preeclampsia remains one of the most common causes of maternal and perinatal mortality worldwide. A significant role in the pathogenesis of this pathology is assigned to placental ischemia and endothelial dysfunction. Therefore, the aim of the present study was to study the effectiveness of asialized erythropoietin and arginase II selective inhibitors: KUD-259 and KUD-974 in the correction of morphofunctional disorders of the cardiovascular system in experimental preeclampsia. Materials and methods:The study was performed in 260 female Wistar rats, each weighing 250-300 g. An AD-MA-like preeclampsia was reproduced in the experiment. To assess the emerging morphofunctional disorders, the following parameters were used: blood pressure, coefficient of endothelial dysfunction, microcirculation in the placenta, proteinuria, fluid content in the omentum, concentration of terminal metabolites in the blood plasma, and morphometric parameters of fetuses. Results and discussion:The administration of arginase II selective inhibitor KUD-974 in combination with asialized erythropoietin leads to a pronounced correction of emerging changes: a decrease in systolic and diastolic blood pressure in 1.5 and 1.7 times, a decrease in proteinuria in 3.6 times and a decrease in fluid content in the omentum. When arginase II selective inhibitor KUD 974 and asialized erythropoietin are used with methyldopa, the positive effects of the former are enhanced. Conclusion:Arginase II selective inhibitors KUD-259 and KUD-974 and asialized erythropoietin have a pronounced positive effect on the correction of morphofunctional disorders in animals with ADMA-like preeclampsia.

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Long term exposure to L-arginine accelerates endothelial cell senescence through arginase-II and S6K1 signaling

Cited by 37 publications

References 34 publications

Angiotensin-(1–7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways

Angiotensin-(1–7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways

Arginase Inhibition Reverses Endothelial Dysfunction, Pulmonary Hypertension, and Vascular Stiffness in Transgenic Sickle Cell Mice

Correction of morphofunctional disorders of the cardiovascular system with asialized erythropoietin and arginase II selective inhibitors KUD 974 and KUD 259 in experimental preeclampsia

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