Arginase Activity Is Increased by Thrombin: A Mechanism for Endothelial Dysfunction in Arterial Thrombosis

Yang, Lin; Lewis, Chandani; Chandrasekharan, Unnikrishnan M.; Kinney, Corttrell M.; DiCorleto, Paul E.; Kashyap, Vikram S.

doi:10.1016/j.jamcollsurg.2006.08.023

Cited by 18 publications

(23 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We used cell culture of endothelial cells derived from rat aortas to elucidate the mechanism of possible impaired NO generation in endothelial cells. Based on our work, 12,14 and results from others, 15 we evaluated the response of RAECs to thrombin, a key enzyme of the coagulation cascade and a potent component of arterial thrombus. We found that thrombin increases the expression of arginase mRNA determined by RT-PCR by nearly sevenfold.…”

Section: Discussionmentioning

confidence: 99%

“…3 Both isomers are found in human umbilical vein endothelial cells. 14,21 Of note, previous experiments on arginase isoforms may have been complicated by smooth muscle contamination of endothelial specimens.…”

Section: Discussionmentioning

confidence: 99%

“…We chose to use a single dose of thrombin based on previous studies. 14,22 Additional mechanistic studies are needed and are currently underway, including the effects of thrombin on the arginase promoter complex and examining L-arginine metabolites. The relevance of these findings to the clinical scenario of thrombosis in diseased arteries and endothelium is unknown.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Arginase blockade lessens endothelial dysfunction after thrombosis

Lewis

Zhu

Pavkov

et al. 2008

Journal of Vascular Surgery

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Arginase blockade lessens endothelial dysfunction after thrombosis

Lewis

Zhu

Pavkov

et al. 2008

Journal of Vascular Surgery

Self Cite

View full text Add to dashboard Cite

show abstract

“…44 High thrombin generation is known to occur in both SCD and thalassemia syndromes. Thrombin itself increases arginase activity in human endothelial cells, 45 and will stimulate vascular smooth muscle cell polyamine synthesis by increasing CAT and ornithine decarboxylase gene expression, thus playing a role in endothelial dysfunction. Additionally, Villagra and colleagues have recently demonstrated that increased platelet activation in SCD correlates strongly with both PH severity and biomarkers of hemolysis.…”

Section: Coagulopathymentioning

confidence: 99%

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Morris¹

2008

Hematology

166

214

View full text Add to dashboard Cite

Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD), with dysfunction of the vascular endothelium as a unifying theme. Specifically, hemolysis-associated low arginine and nitric oxide (NO) bioavailability, amplified by NO synthase uncoupling, elevated arginase activity, superoxide production, oxidative stress, accumulation of arginine analogs such as asymmetric dimethylarginine, ischemia-reperfusion injury, inflammation, apolipoprotein A-1 depletion, and a hypercoagulable state are significant mechanisms contributing to endothelial dysfunction. Genetic polymorphisms also influence disease severity. Clearly the variable spectrum of disease is the consequence of multiple events and genetic susceptibility that go beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Recent studies begin to demonstrate overlap among these seemingly unrelated processes. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a common denominator in the pathogenesis of vasculopathy in SCD. The consequences of decreased NO bioavailability include endothelial cell activation, upregulation of the potent vasoconstrictor endothelin-1, vasoconstriction, platelet activation, increased tissue factor, and activation of coagulation, all of which ultimately translate into the clinical manifestations of SCD. Evidence supporting vasculopathy subphenotypes in SCD, including pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke, will be reviewed and relevance to other hemolytic disorders including the thalassemia syndromes will be considered.

show abstract

“…ARGINASE IS A HYDROLYTIC ENZYME responsible for conversion of L-arginine to urea and L-ornithine (13,46). Arginase can reciprocally regulate nitric oxide (NO) production in endothelial cells by competing with nitric oxide synthase (NOS) for the substrate L-arginine (2,3,33).…”

mentioning

confidence: 99%

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Shatanawi¹,

Romero²,

Iddings³

et al. 2011

American Journal of Physiology-Cell Physiology

125

114

View full text Add to dashboard Cite

Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 μM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 μM). Blockade of ANG II AT(1) receptors or transfection with small interfering RNA (siRNA) for Gα12 and Gα13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Gαq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 μM) or Rho kinase (ROCK) (Y-27632, 10 μM; H1152, 0.5 μM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 μM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 μg·kg(-1)·day(-1)) or arginase (ABH, 8 mg·kg(-1)·day(-1)) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Gα12/13 G proteins coupled to AT(1) receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction.

show abstract

Arginase Activity Is Increased by Thrombin: A Mechanism for Endothelial Dysfunction in Arterial Thrombosis

Cited by 18 publications

References 23 publications

Arginase blockade lessens endothelial dysfunction after thrombosis

Arginase blockade lessens endothelial dysfunction after thrombosis

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

Contact Info

Product

Resources

About