Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction

• Published in: PloS one Vol. 10; no. 10; p. e0140697
• Main Authors: Scioli, Maria Giovanna, Lo Giudice, Pietro, Bielli, Alessandra, Tarallo, Valeria, De Rosa, Alfonso, De Falco, Sandro, Orlandi, Augusto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.10.2015; Public Library of Science (PLoS)
• Subjects: Adhesion; Analysis; Angiogenesis; Animals; Antioxidants; Blood; Blood flow; Blood Flow Velocity - drug effects; Carnitine; Carnitine - analogs & derivatives; Carnitine - pharmacology; Cell adhesion & migration; Deprivation; Dermis - injuries; Dermis - metabolism; Dermis - pathology; Dosage and administration; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Health care; Humans; Inhibition; Ischemia; Kinases; Leukocytes; Levocarnitine; Male; Management; Microcirculation - drug effects; Microvasculature; Mitochondria; NAD(P)H oxidase; NADPH Oxidase 4; NADPH Oxidases - metabolism; Neovascularization, Physiologic - drug effects; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - biosynthesis; Nitric-oxide synthase; NOX4 protein; Oxidases; Oxidation; Oxidative stress; Oxygen; Pathology; Pharmacology; Placenta; Placenta Growth Factor; Pregnancy Proteins - biosynthesis; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors; Reduction; Rodents; Skin; Ulcers; Up-Regulation - drug effects; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor Receptor-1 - biosynthesis; Vascular Endothelial Growth Factor Receptor-2 - biosynthesis; Vasoconstriction; Vasodilation; Viability; Wound care; Wound healing; Wound Healing - drug effects; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140697

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. 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. 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.