Homoarginine administration reduces neointimal hyperplasia in a rat model of carotid artery balloon injury

Background. Homoarginine is an L-arginine homologue derived from lysine. Its physiological role is still in part unknown, but the structural similarity to L-arginine suggests that it may be an alternative substrate for enzymes that use L-arginine, such as nitric oxide synthase. Data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study have shown that low serum concentrations of homoarginine are an independent risk factor for all-cause and cardiovascular mortality. The strong association between low homoarginine levels and cardiovascular outcomes raises the question if this molecule could be relevant in the pathophysiology of vascular disease. Neointimal hyperplasia is an exaggerated inflammatory healing response after vascular injury. Of particular clinical interest is neointimal hyperplasia after balloon angioplasty and vascular stent deployment, since this may limit therapeutic success. Several studies have demonstrated that L-arginine supplementation is able to inhibit neointimal formation in experimental models of balloon injury. Aim. The purpose of this study was to evaluate the effect of homoarginine on neointimal formation in a rat model of carotid artery balloon injury. Methods. Thirty-six male Sprague-Dawley rats underwent endothelial injury at the level of the left carotid, followed by the insertion of a cannula into the right jugular vein. The cannula was connected to an osmotic infusion pump containing saline, L-arginine (30 mg/kg per day) or homoarginine (30 mg/kg per day). Fourteen days after balloon injury, blood was collected and left carotids were harvested for histological analyses. Systolic blood pressure was measured before and at the end of drug treatments. Results. As expected, L-arginine administration significantly reduced the carotid intimal/medial area ratio compared to that of controls (0.69±0.40 vs 1.33±0.67, p<0.05). Homoarginine-treated rats also showed a significant reduction of the vessel intimal/medial area ratio versus controls (0.71±0.43 vs 1.33±0.67, p<0.05). No signs of toxicity and no changes in systolic blood pressure by treatment were detected among groups. Homoarginine serum concentrations were dramatically high only in homoarginine-treated rats (38.5±8.4 mM,1.2±0.1 mM and 1.1±0.3 mM in homoarginine, L-arginine and control groups, respectively; p<0.0001). On the contrary, plasma L-arginine level was significantly increased in both L-arginine and homoarginine group compared to controls (137.3±15.6 mM,139.3±25.9 mM and 116.2±12.9 mM in L-arginine, homoarginine and control group, respectively; p<0.05). Moreover, in the homoarginine group a significant increase in serum concentration of ornithine was detected compared to control and L-arginine group (91.0±12.9 mM, 73.8±11.7 mM and 69.4±9.2 mM in homoarginine, L-arginine and control groups, respectively; p<0.05). Finally, L-arginine- and homoarginine-treated rats displayed higher nitrite levels compared to controls (2.4±1.2 mM, 2.2±0.8 mM and 1.1±0.4 mM in L-arginine, homoarginine and control groups, respectively; p<0.05). Conclusions. Our study shows that in vivo homoarginine administration is able to inhibit neointimal formation in balloon-injured rat carotid arteries. Moreover, our data indicate that this effect could be due, at least in part, to an increased availability of L-arginine and nitric oxide production. Taken together, these evidences corroborate previous clinical data showing an association between homoarginine levels, endothelial function and cardiovascular health.