Propionyl-L-carnitine improves postischemic blood flow recovery and arteriogenetic revascularization and reduces endothelial NADPH-oxidase 4-mediated superoxide production.
OBJECTIVE
The beneficial effect of the natural compound propionyl-l-carnitine (PLC) on intermittent claudication in patients with peripheral arterial disease is attributed to its anaplerotic function in ischemic tissues, but inadequate information is available concerning action on the vasculature.


RESULTS
We investigated the effects of PLC in rabbit hind limb collateral vessels after femoral artery excision, mouse dorsal air pouch, chicken chorioallantoic membrane, and vascular cells by angiographic, Doppler flow, and histomorphometrical and biomolecular analyses. PLC injection accelerated hind limb blood flow recovery after 4 days (P<0.05) and increased angiographic quadriceps collateral vascularization after 7 days (P<0.001) Histomorphometry confirmed the increased vascular area (P<0.05), with unchanged intramuscular capillary density. PLC-induced dilatative adaptation, and growth was found associated with increased inducible nitric oxide synthase and reduced arterial vascular endothelial growth factor and intracellular adhesion molecule-1 expression. PLC also increased vascularization in air pouch and chorioallantoic membrane (P<0.05), particularly in large vessels. PLC increased endothelial and human umbilical vascular endothelial cell proliferation and rapidly reduced inducible nitric oxide synthase and NADPH-oxidase 4-mediated reactive oxygen species production in human umbilical vascular endothelial cells; NADPH-oxidase 4 also regulated NF-kappaB-independent intracellular adhesion molecule-1 expression.


CONCLUSIONS
Our results provided strong evidence that PLC improves postischemic flow recovery and revascularization and reduces endothelial NADPH-oxidase-related superoxide production. We recommend that PLC should be included among therapeutic interventions that target endothelial function.
Stasi
Maria Antonietta
MA
Dept. of Biopathology and Image Diagnostics, Tor Vergata University of Rome, Via Montpellier, 00133 Rome, Italy.
Scioli
Maria Giovanna
MG
Arcuri
Gaetano
G
Mattera
Giovan Giuseppe
GG
Lombardo
Katia
K
Marcellini
Marcella
M
Riccioni
Teresa
T
De Falco
Sandro
S
Pisano
Claudio
C
Spagnoli
Luigi Giusto
LG
Borsini
Franco
F
Orlandi
Augusto
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001808:Blood Vessels / Q000502:physiology*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D003097:Collateral Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; C003223:propionylcarnitine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D002331:Carnitine