L-arginine prevents heart transplant arteriosclerosis by modulating the vascular cell proliferative response to insulin-like growth factor-I and interleukin-6.
BACKGROUND
L-arginine, a nitric oxide precursor, inhibits myointimal hyperplasia induced by balloon injury in native vessels. No studies are published on L-arginine effects on transplant arteriosclerosis. Insulin-like growth factor-I and interleukin-6 are mitogenic for smooth muscle cells and are involved in the cell-mediated and humoral immune response.


METHODS
New Zealand White rabbits received cardiac allografts from Dutch Belted rabbits. All animals were fed a 0.5% cholesterol diet and received drinking water with (eight pairs) or without (eight pairs) L-arginine (2.5%) from day 7 to until they were killed at day 42. The recipients received cyclosporine A 10 mg/kg/day from transplantation until the time they were killed.


RESULTS
Dietary L-arginine reduces myointimal hyperplasia in allograft coronary arteries from 44% +/- 4% in the non-L-arginine group to 16% +/- 2% (p < 0.002). The L-arginine significantly inhibits graft vascular cell proliferation induced by (1) insulin-like growth factor-I, from 328% +/- 66% to 154% +/- 28% (p < 0.05), (2) interleukin-6, from 376% +/- 97% to 138% +/- 30% (p < 0.05) and (3) the combination of insulin-like growth factor-I and interleukin-6 from 710% +/- 201% to 226% +/- 72% (p < 0.05). In recipient native aorta explants L-arginine also abolishes vascular cell proliferation stimulated by insulin-like growth factor-I and interleukin-6. The rejection grading is similar in the L-arginine (2.9 +/- 0.1) and control groups (2.7 +/- 0.1). Class II major histocompatibility antigen expression, T-lymphocyte, and macrophage infiltration in the cardiac allograft are unaffected by L-arginine. However, the diet significantly increased plasma nitric oxide from 15.4 +/- 2.3 to 45.1 +/- 11 mumol (p < 0.05).


CONCLUSIONS
Dietary L-arginine attenuates transplant arteriosclerosis in vivo without affecting rejection. The protective effect seen in these experiments may relate to the generation of sufficient nitric oxide to prevent smooth muscle cell response to mitogens like insulin-like growth factor-I and interleukin-6.
Lou
H
H
Department of Surgery, Georgetown University Medical Center, Washington, DC 20007, USA.
Kodama
T
T
Wang
Y N
YN
Katz
N
N
Ramwell
P
P
Foegh
M L
ML
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects; D001120:Arginine / Q000627:therapeutic use*; D003324:Coronary Artery Disease / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D011183:Postoperative Complications / Q000517:prevention & control; D011817:Rabbits; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D016572:Cyclosporine; D001120:Arginine