Hypobaric hypoxia induced arginase expression limits nitric oxide availability and signaling in rodent heart

Singh, Manjulata; Padhy, Gayatri; Vats, Praveen; Bhargava, Kalpana; Sethy, Niroj Kumar

doi:10.1016/j.bbagen.2014.01.015

Cited by 20 publications

(23 citation statements)

References 36 publications

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“…It was reported previously that hypoxia contributed to arginase activation induced by the ROS burst through c-Jun and AP-1 interaction [9]. We have shown that RCE treatment is able to attenuate ROS intensity in both hypoxic lung [16] and heart tissues.…”

Section: Discussionmentioning

confidence: 54%

“…Arginase inhibition has been shown to both improve NO availability by shifting L-arginine utilization from arginase to eNOS and to decrease oxidative stress in hypoxic heart tissue [9]. Taken together, these observations suggest that inhibition of arginase activity is a potential therapeutic strategy in hypoxia-associated heart disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Once activated, arginase competes with eNOS and reacts with L-arginine, resulting in reduced NO availability. Thus, arginase plays a crucial role in adaptation to hypoxia [9]. Reactive oxygen species (ROS) are also associated with pulmonary artery vasoconstriction and offsetting of NO signaling [10].…”

Section: Introductionmentioning

confidence: 99%

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Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway

Hsu

Chang

et al. 2017

BMC Complement Altern Med

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Background Rhodiola crenulata is traditionally used as a folk medicine in Tibet for preventing high-altitude illnesses, including sudden cardiac death (SCD). The cardio-protective effects of Rhodiola crenulata root extract (RCE) against hypoxia in vivo have been recently confirmed. However, the way in which RCE produces these effects remains unclear. The present study is designed to confirm the protective effects of RCE on the heart in acute hypobaric hypoxia exposure and examine the mechanisms by which this occurs.MethodsSprague–Dawley (SD) rats were pretreated with or without RCE and then exposed to a simulated altitude of 8000 m in a hypobaric hypoxia chamber for 9 h. The expression of cardiac arginase 1 (Arg-1) and endothelial nitric oxide synthase (eNOS) and the activity of associated signaling pathways was examined.ResultsHypoxia reduced cardiac eNOS phosphorylation and increased Arg-1 expression, but both responses were reversed by RCE pre-treatment. In addition, RCE decreased the hypoxia-induced oxidative stress markers of reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and protein carbonyl content. Furthermore, RCE protected cardiomyocytes from hypoxia-induced cardiac apoptosis and restored the phosphorylation level of AKT and p38 MAPK as well as the superoxide dismutase 2 (SOD2) content in hypoxic animals.ConclusionThe findings provide evidence that the effects of Rhodiola crenulata against altitude illness are partially mediated by modulation of eNOS and Arg-1 pathways in the heart.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1524-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway

Hsu

Chang

et al. 2017

BMC Complement Altern Med

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“…Systemic treatment of rat with an arginase inhibitor N-(ω)-hydroxy-nor-L-arginine (nor-NOHA) was shown to significantly prevent both hypoxia-increased tissue level of ROS and lipid peroxides in hypoxic hearts. Nor-NOHA treatment also significantly ameliorated the peroxynitrite formation in hypoxic hearts (Singh et al , 2014). Further, nitroglycerin (NTG)-induced increases of ROS levels in aorta isolated from wild type mice were not observed in aorta pretreated with the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC), nor in aorta isolated from Arg2 –/– mice.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia-inducible factor 2α (HIF-2α) likely mediates this induction since the silencing of HIF-2α but not HIF-1α prevented activation of arginase 2 by hypoxia (Krotova et al , 2010). In contrast, hypoxia-induced enhancement of arginase 1 expression and arginase activity was found in rat cardiac and aortic tissue, which was linked to the hypoxia-mediated c-Jun recruitment to AP-1 binding site on ARG1 promoter (Singh et al , 2014). The discrepancy in arginase isoforms induced by hypoxia can be explained by reports that arginase 1 is the predominant isoforms in the rat endothelium while arginase 2 is the major isoforms in human aortic and human umbilical vein endothelial cells (Ming et al , 2004; Ryoo et al , 2006; Gao et al , 2007).…”

Section: Discussionmentioning

confidence: 99%

Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia

Wang

Bhatta

Toque

et al. 2015

Microvascular Research

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Hypoxia-induced arginase elevation plays an essential role in several vascular diseases but influence of arginase on hypoxia-mediated angiogenesis is completely unknown. In this study, in-vitro network formation in bovine aortic endothelial cells (BAEC) was examined after exposure to hypoxia for 24 hours with or without arginase inhibition. Arginase activity, protein levels of the two arginase isoforms, eNOS, and VEGF as well as production of NO and ROS were examined to determine the involvement of arginase in hypoxia-mediated angiogenesis. Hypoxia elevated arginase activity and arginase 2 expression but reduced active p-eNOSSer1177 and NO levels in BAEC. Additionally, both VEGF protein levels and endothelial elongation and network formation were reduced with continued hypoxia, whereas ROS levels increased and NO levels decreased. Arginase inhibition limited ROS, restored NO formation and VEGF expression and prevented the reduction of angiogenesis. These results suggest a fundamental role of arginase activity in regulating angiogenic function.

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S1P prophylaxis mitigates acute hypobaric hypoxia‐induced molecular, biochemical, and metabolic disturbances: A preclinical report

2016

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Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 6 20 g) were preconditioned with 1, 10, and 100 lg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 mg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)21a and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1a/Hsp70 induction. Conclusively, systemic preconditioning with 1 lg/kg b.w. S1P in rats protects against acute HHinduced pathological disturbances. V C 2016 IUBMB Life, 68(5): [365][366][367][368][369][370][371][372][373][374][375] 2016

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Hypobaric hypoxia induced arginase expression limits nitric oxide availability and signaling in rodent heart

Cited by 20 publications

References 36 publications

Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway

Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway

Arginase inhibition enhances angiogenesis in endothelial cells exposed to hypoxia

S1P prophylaxis mitigates acute hypobaric hypoxia‐induced molecular, biochemical, and metabolic disturbances: A preclinical report

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