The nitric oxide precursor L-arginine reduces expression of hyaluronan synthase in experimental vein bypass grafts.
BACKGROUND
The success of vascular bypass procedures is limited by the development of intimal hyperplasia (IH). The nitric oxide (NO) precursor, L-arginine (L-ARG) significantly reduces IH in both arteries and experimental vein grafts; however, the precise mechanism has yet to be elucidated. Hyaluronan synthase-1 (HAS-1) is one of the two enzymes believed to be responsible for making hyaluronan, a key component extracellular matrix composition.


OBJECTIVE
To determine how L-ARG supplementation affects the gene expression of HAS-1 in experimental vein grafts.


METHODS
Thirty-four male New Zealand white rabbits were divided into three groups: control (no operation, regular chow and water, n = 4); L-ARG supplemented (n = 15); and no L-ARG (n = 15). The latter two groups underwent a right interposition carotid bypass using jugular vein. Vein grafts were harvested at 7, 14, and 21 days after surgery. Ribonuclease protection assays were performed using 32P-labeled riboprobes for HAS-1 and 18S rRNA as an internal control and expressed as a ratio (HAS-1/rRNA).


RESULTS
There was a significant rise in HAS-1 expression in the vein grafts 7 (1.57 +/- 0.5), 14 (0.7 +/- 0.2), and 21 days (2.82 +/- 0.7) after grafting compared to control (0.14 +/- 0.08) (P < 0.05). L-ARG-supplemented animals had a significant decrease in HAS-1 expression at 21 days (0.65 +/- 0.1) compared to nonsupplemented vein grafts (2.82 +/- 0.7) (P < 0.02).


CONCLUSIONS
These results demonstrate for the first time a significant rise in HAS expression in the early experimental vein grafts. Furthermore, L-ARG supplementation significantly diminishes the expression of HAS at 21 days. These results may represent a potential mechanism by which augmentation of the L-ARG/NO pathway inhibits IH in experimental vein grafts and may ultimately provide for improved therapeutic interventions in alleviating IH.
Dattilo
J B
JB
Hunter H. McGuire Veterans Administration Medical Center, Richmond, Virginia, USA.
Dattilo
M P
MP
Crane
J T
JT
Yager
D R
DR
Makhoul
R G
RG
D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology*; D002339:Carotid Arteries / Q000601:surgery; D015870:Gene Expression / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics*; D016695:Glycosyltransferases; D000076002:Hyaluronan Synthases; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007527:Isoenzymes / Q000235:genetics*; D007601:Jugular Veins / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery*; D008297:Male; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D014166:Transferases; D014656:Vascular Surgical Procedures; D029867:Xenopus Proteins
D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D029867:Xenopus Proteins; D009569:Nitric Oxide; D001120:Arginine; D014166:Transferases; D016695:Glycosyltransferases; D014453:Glucuronosyltransferase; C056944:HAS1 protein, Xenopus; D000076002:Hyaluronan Synthases