Rapid and efficient vascular transport of arginine polymers inhibits myointimal hyperplasia.
BACKGROUND
We recently discovered that short polymers of arginine efficiently translocate across the cytoplasmic membrane independent of the basic amino acid transporter. We evaluated the kinetics and biological effects of heptamers of L-arginine and D-arginine (L-R7 and D-R7, respectively) in vascular cells. We assessed the effects of these peptides on the NO synthesis pathway and vascular cell proliferation.


RESULTS
Human umbilical vein endothelial cell and rabbit vascular segments were incubated in medium containing biotin-labeled L-R7 or D-R7. Both polymers rapidly translocated through the vessel wall and into the vascular cells in a dose- and time-dependent fashion. At a dose of 10 micromol/L for 30 minutes, 100% of the endothelial cells showed evidence of cytoplasmic and nuclear localization of the peptides. To evaluate the biological effects of the polymer translocation on myointimal formation, rabbit jugular vein segments were incubated with polymers (10 micromol/L, 30 minutes) or vehicle before arterial interposition grafting. Planimetric measurement 28 days after surgery revealed that L-R7 and D-R7 substantially reduced myointimal formation compared with the control condition (intima/media ratio: control 1. 50.5, L-R7 0.40.2, and D-R7 0.80.2; P:<0.05). Furthermore, basal nitrate and nitrite production from L-R7-treated grafts was significantly higher than that from both control and D-R7-treated veins. Studies in vitro of cultured vascular smooth muscle cells revealed that both polymers also exhibit an NO-independent inhibition of vascular smooth muscle cell proliferation.


CONCLUSIONS
Short polymers of arginine have the unique ability of vascular cell translocation, and they also have direct biological effects. These attributes are potentially useful in treating myointimal hyperplasia.
Uemura
S
S
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5246, USA.
Fathman
C G
CG
Rothbard
J B
JB
Cooke
J P
JP
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001710:Biotin; D002339:Carotid Arteries / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006083:Graft Occlusion, Vascular / Q000517:prevention & control; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control*; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D013696:Temperature; D014182:Transplantation, Autologous; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D009842:Oligopeptides; D010455:Peptides; C416678:heptaarginine amide; D001710:Biotin