Therapeutic approach against intimal hyperplasia of vein grafts through endothelial nitric oxide synthase/nitric oxide (eNOS/NO) and the Rho/Rho-kinase pathway.
Late graft failure of autologous vein grafts is associated with intimal hyperplasia resulting from the migration and proliferation of vascular smooth muscle cells (VSMCs). Endothelial nitric oxide synthase (eNOS) is an enzyme that synthesizes nitric oxide (NO). An impairment of NO-mediated vasorelaxation and increases in cell proliferation occurs in vein grafts after the surgery and these pathophysiological changes cause intimal thickening. The Rho/Rho-kinase pathway negatively regulates eNOS and is involved in intimal hyperplasia. Several studies have been conducted with the goal of controlling intimal hyperplasia targeting eNOS/NO and the Rho/Rho-kinase pathway. The oral administration of drugs, such as Rho-kinase inhibitor, L: -arginine, beta-blocker and statins, significantly suppressed intimal thickening in animal models. This study revealed that statins upregulate eNOS through Rho-kinase inhibition to suppress intimal hyperplasia. The intraluminal gene transfer of eNOS inhibited intimal hyperplasia, thereby reducing the cell proliferation. These approaches are thus considered to be potentially promising therapeutic modalities for graft failure.
Sugimoto
Masayuki
M
Department of Vascular Surgery, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
Yamanouchi
Dai
D
Komori
Kimihiro
K
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000201:enzymology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006083:Graft Occlusion, Vascular / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006965:Hyperplasia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014182:Transplantation, Autologous; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047428:Protein Kinase Inhibitors; D009569:Nitric Oxide; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; C049347:fasudil