Effect of Arginine on Advanced Glycation End Products-Induced Vascular Damage

Diabetes mellitus (DM) is the 4th leading cause of death in Taiwan. Cardiovascular events initiated with endothelial dysfunction are the major cause of mortality in DM. Hyperglycemia and oxidative stress resulted from DM have an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation end products (AGEs) in body tissues. Recent studies found that AGEs enhanced the expression of angiotensin II (Ang II), and Ang II promotes the expression of AGEs receptors. The interaction of AGEs with AGEs receptor initiates the release of pro-inflammatory molecules and free radicals that contribute towards the pathology of atherosclerosis. This may possibly explain why DM patients are usually hypertensive. Arginine (Arg) is a semi-essential amino acid with numerous useful physiologic properties. Arg is the substrate of endothelial nitric oxide (NO) synthase and the precursor of NO. Previous reports showed that Arg had anti-hypertensive effect in hypertensive or DM patients. Some studies found that endothelial function improved when Arg was administered. However, most studies evaluating the effect of Arg on endothelial function focused exclusively on DM or hypertension. Studies investigating the effects of Arg on co-morbidities were rare. At present, no study investigates the effect of Arg or NO on the interaction between AGEs and Ang II. Therefore, we plan to investigate the effect of Arg on AGEs and Ang II-induced endothelial dysfunction and inflammatory reaction. This study will be carried out in 3 consecutive years. In the first year, we will inject AGEs directly to rats to investigate the effect of Arg on AGE-induced oxidative stress, inflammatory reaction and endothelial function. In the second year, congenital hypertensive rats are induced diabetic to investigate the possible role of Arg on the interaction of AGEs and Ang II in diabetes complicated with hypertension. In the third year, an in vitro study with transwell and human umbilical vein endothelial cell will be used as a model system, to observe the influence of Arg on endothelium adhesion molecule expression and monocyte transmigration under the stimulation of AGEs and Ang II. This will be the first study to investigate the effects of Arg and NO on the mechanism of AGEs and Ang II interactions. The results of this study will provide useful information for the clinical applications in DM patients and diabetic patients complicated with hypertension.