title: Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction.
abstract: BACKGROUND
  Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery.
  
  
  RESULTS
  We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction.
  
  
  CONCLUSIONS
  PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. Antioxidant therapy and pharmacological targeting of endothelial dysfunction may represent a promising tool for the treatment of delayed wound healing or chronic ulcers.
authors.affiliation: Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Scioli
authors.affiliation: Sigma-Tau S.p.A., Pomezia, Rome, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Lo Giudice
authors.affiliation: Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bielli
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Genetics and Biophysics "A. Buzzati Traverso", Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.affiliation: Sigma-Tau S.p.A., Pomezia, Rome, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Rosa
authors.affiliation: Consiglio Nazionale delle Ricerche, Institute of Genetics and Biophysics "A. Buzzati Traverso", Naples, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: De Falco
authors.affiliation: Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy; Policlinic of Tor Vergata, Anatomic Pathology, Rome, Italy.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020405:Dermis / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000072483:Placenta Growth Factor; C003223:propionylcarnitine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; C000602029:Kdr protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D002331:Carnitine