Effects of L-arginine on the endogenous angiogenic response in a model of hypercholesterolemia.
BACKGROUND
The angiogenic properties of vascular endothelial growth factor and fibroblast growth factor-2 are mediated in part through nitric oxide release, whose availability is decreased in endothelial dysfunction associated with advanced coronary artery disease. We examined the influence of L-arginine supplementation on the endogenous angiogenic response to ischemia in a porcine model of hypercholesterolemia.


METHODS
Eighteen Yucatan pigs were fed either a normal (NORM, n=6) or a high-cholesterol diet, with (CHOL-ARG, n=6) or without (CHOL, n=6) L-arginine (100 mg/kg/day), throughout the experiment. All pigs underwent ameroid constrictor placement on the circumflex artery (LCx). Seven weeks later, endothelium-dependent coronary microvascular responses to fibroblast growth factor-2 and vascular endothelial growth factor were assessed by videomicroscopy. Perfusion was assessed with radioactive microspheres; angiogenesis was evaluated by platelet-endothelial cell adhesion molecule-1 (CD-31) staining. Regional myocardial function was assessed by sonomicrometry. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase was measured by Western blot analyses.


RESULTS
Pigs from the CHOL group showed significant endothelial dysfunction in the LCx territory. The dysfunction was normalized partially by L-arginine supplementation, which restored the response in the LCx territory to the level of the nonischemic anterior wall. L-arginine supplementation resulted in increases of perfusion, density of capillary endothelial, and level of endothelial nitric oxide synthase in the ischemic region. Despite these findings, no improvement in myocardial regional function was found.


CONCLUSIONS
L-arginine supplementation can partially restore endothelium-dependent vasorelaxation and improve myocardial perfusion in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with growth factor therapy for end-stage coronary artery disease.
Nakai
Yasunari
Y
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Voisine
Pierre
P
Bianchi
Cesario
C
Xu
Shu-Hua
SH
Feng
Jun
J
Malik
Tamer
T
Rosinberg
Audrey
A
Sellke
Frank W
FW
D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000503:physiopathology; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology*; D008833:Microcirculation / Q000187:drug effects; D009200:Myocardial Contraction; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013552:Swine; D013556:Swine, Miniature; D014664:Vasodilation / Q000187:drug effects
D001120:Arginine; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III