Arginase blockade lessens endothelial dysfunction after thrombosis

Lewis, Chandani; Zhu, Weifei; Pavkov, Mircea L.; Kinney, Corttrell M.; DiCorleto, Paul E.; Kashyap, Vikram S.

doi:10.1016/j.jvs.2008.02.030

Cited by 11 publications

(13 citation statements)

References 22 publications

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“…Of note, rat endothelium exposed to thrombin for 6 h led to increased arginase I mRNA (6.8-fold) and arginase I protein levels (2.1-fold) (27). We believe that thrombin plays a central role in thrombus-induced endothelial dysfunction and investigated the molecular mechanisms of arginase changes after thrombin exposure.…”

Section: Discussionmentioning

confidence: 91%

“…We have previously shown that arterial thrombosis leads to endothelial dysfunction secondary to decreased nitric oxide bioactivity, and that this can be ameliorated via L-arginine supplementation or arginase blockade (12,23,27,39,56). Of note, rat endothelium exposed to thrombin for 6 h led to increased arginase I mRNA (6.8-fold) and arginase I protein levels (2.1-fold) (27).…”

Section: Discussionmentioning

confidence: 98%

“…RAECs were primary cultured as described previously (27). Isolated RAECs were initially plated onto T75 flasks in a 37°C, humidified, 5% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

“…We have shown that exposure of RAECs to thrombin, an active component of a thrombus, upregulates arginase I mRNA and protein expression without affecting eNOS (27). To evaluate the function of the enzyme stimulated by thrombin, arginase activity was measured by the conversion of L-[guanidine-14 C] arginine to [ 14 C]urea (24,34).…”

Section: Thrombin Stimulates Arginase I Transcription Activation and mentioning

confidence: 99%

“…Recently, we found that exposure of rat aortic endothelial cells (RAECs) to thrombin upregulated arginase I mRNA and protein expression. Furthermore, both specific and nonspecific arginase inhibitors ameliorated endothelial dysfunction after thrombosis in rats (27,56). However, the molecular mechanisms of thrombin-induced upregulation of arginase I are unknown.…”

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confidence: 99%

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Thrombin induces endothelial arginase through AP-1 activation

Zhu

Chandrasekharan²,

Bandyopadhyay³

et al. 2010

American Journal of Physiology-Cell Physiology

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Arterial thrombosis is a common disease leading to severe ischemia beyond the obstructing thrombus. Additionally, endothelial dysfunction at the site of thrombosis can be rescued by l-arginine supplementation or arginase blockade in several animal models. Exposure of rat aortic endothelial cells (RAECs) to thrombin upregulates arginase I mRNA and protein levels. In this study, we further investigated the molecular mechanism of thrombin-induced arginase changes in endothelial cells. Thrombin strikingly increased arginase I promoter and enzyme activity in primary cultured RAECs. Using different deletion and point mutations of the promoter, we demonstrated that the activating protein-1 (AP-1) consensus site located at -3,157 bp in the arginase I promoter was a thrombin-responsive element. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed that upon thrombin stimulation, c-Jun and activating transcription factor-2 (ATF-2) bound to the AP-1 site, which initiated the transactivation. Moreover, loss-of-function studies using small interfering RNA confirmed that recruitment of these two transcription factors to the AP-1 site was required for thrombin-induced arginase upregulation. In the course of defining the signaling pathway leading to the activation of AP-1 by thrombin, we found thrombin-induced phosphorylation of stress-activated protein kinase/c-Jun-NH(2)-terminal kinase (SAPK/JNK or JNK1/2/3) and p38 mitogen-activated protein kinase, which were followed by the phosphorylation of both c-Jun and ATF-2. These findings reveal the basis for thrombin induction of endothelial arginase I and indicate that arginase inhibition may be an attractive therapeutic alternative in the setting of arterial thrombosis and its associated endothelial dysfunction.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 98%

“…RAECs were primary cultured as described previously (27). Isolated RAECs were initially plated onto T75 flasks in a 37°C, humidified, 5% CO 2 incubator.…”

Section: Methodsmentioning

confidence: 99%

Section: Thrombin Stimulates Arginase I Transcription Activation and mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Thrombin induces endothelial arginase through AP-1 activation

Zhu

Chandrasekharan²,

Bandyopadhyay³

et al. 2010

American Journal of Physiology-Cell Physiology

Self Cite

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Pharmacokinetics and Pharmacodynamics of Promising Arginase Inhibitors

Abdelkawy

Lack

Elbarbry

2016

Eur J Drug Metab Pharmacokinet

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Up-regulation of arginase activity in several chronic disease conditions, including cancer and hypertension, may suggest new targets for treatment. Recently, the number of new arginase inhibitors with promising therapeutic effects for asthma, cancer, hypertension, diabetes mellitus, and erectile dysfunction has shown a remarkable increase. Arginase inhibitors may be chemical substances, such as boron-based amino acid derivatives, α-difluoromethylornithine (DMFO), and Nω-hydroxy-nor-L-arginine (nor-NOHA) or, of plant origin such as sauchinone, salvianolic acid B (SAB), piceatannol-3-O-β-D-glucopyranoside (PG) and obacunone. Despite their promising therapeutic potential, little is known about pharmacokinetics and pharmacodynamics of some of these agents. Several studies were conducted in different animal species and in vitro systems and reported significant differences in pharmacokinetics and pharmacodynamics of arginase inhibitors. Therefore, extra caution should be considered before extrapolating these studies to human. Physicochemical and pharmacokinetic profiles of some effective arginase inhibitors make it challenging to formulate stable and effective formulation. In this article, existing literature on the pharmacokinetics and pharmacodynamics of arginase inhibitors were reviewed and compared together with emphasis on possible drug interactions and solutions to overcome pharmacokinetics challenges and shortage of arginase inhibitors in clinical practice.

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