Endothelial arginase: A new target in atherosclerosis
- 135 Downloads
Decreased endothelial nitric oxide (NO) bioavailability as it relates to endothelial dysfunction plays an important role in various cardiovascular disorders, including atherosclerosis. Recent research has provided evidence that endothelial dysfunction in atherosclerosis is not primarily caused by decreased endothelial NO synthase (eNOS) gene expression, but rather deregulation of eNOS enzymatic activity, which contributes to the increased oxidative stress in atherosclerosis. Among other mechanisms, the substrate L-arginine is an important limiting factor for NO production. Emerging evidence demonstrates that L-arginine is not only converted to NO via eNOS, but also metabolized to urea and L-ornithine via arginase in endothelial cells. Hence, arginase competes with eNOS for the substrate L-arginine, resulting in deceased NO production. There are an increasing number of studies showing that enhanced arginase gene expression and/or activity contribute to endothelial dysfunction in various cardiovascular disorders, including atherosclerosis. Thus, endothelial arginase may represent a new therapeutic target in atherosclerosis.
Unable to display preview. Download preview PDF.
References and Recommended Reading
- 4.Yang Z, Luscher TF: Vascular endothelium. In PanVascularMedicine. Edited by Lanzer P, Topol EJ. Berlin-Heidelberg-New York: Springer; 2002:190–204.Google Scholar
- 13.Ming XF, Barandier C, Viswambharan H, et al.: Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation 2004, 110:3708–3714. This is the first study showing that endothelial arginase activity is regulated by the Rho/ROCK pathway. Arginase activity is increased in atherosclerotic aortas in ApoE-/-mice and plays a substantial role in endothelial dysfunction in atherosclerosis.PubMedCrossRefGoogle Scholar
- 24.Loscalzo J: Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol 2003, 23:3–5. A critical editorial comment analyzing controversial results with L-arginine supplemental therapy obtained from experimental and clinical studies.PubMedCrossRefGoogle Scholar
- 28.Walker HA, McGing E, Fisher I, et al.: Endotheliumdependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: lack of effect of oral L-arginine on endothelial function, oxidative stress and exercise performance. J Am Coll Cardiol 2001, 38:499–505.PubMedCrossRefGoogle Scholar
- 46.Johnson FK, Johnson RA, Peyton KJ, et al.: Arginase inhibitionrestores arteriolar endothelial function in Dahl ratswith salt-induced hypertension. Am J Physiol Regul Integr Comp Physiol 2004, Dec 9, [Epub ahead of print].Google Scholar
- 47.Demougeot C, Prigent-Tessier A, Marie C, et al.: Arginase inhibition reduces endothelial dysfunction and blood pressure rising in spontaneously hypertensive rats. J Hypertens 2005, 23:971–978. An important study demonstrating that arginase expression and activity are increased in spontaneous hypertensive rats, and treatment of the rat with an arginase inhibitor improves endothelial function and decreases blood pressure in the animals.PubMedCrossRefGoogle Scholar
- 49.Morris CR, Kato GJ, Poljakovic M, et al.: Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005, 294:81–90. The first clinical study showing that increased arginase activity in plasma and red blood cells is independently associated with pulmonary hypertension and mortality in patients with sickle cell disease.PubMedCrossRefGoogle Scholar
- 50.Nelin LD, Chicoine LG, Reber KM, et al.: Cytokineinducedendothelial arginase expression is dependent onepidermal growth factor receptor. Am J Respir Cell Mol Biol 2005, Jun 30, [Epub ahead of print].Google Scholar