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

Abstract

BackgroundImpaired 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.Methods and ResultsWe 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.ConclusionPLC 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.

Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model

“…ROS are produced by several enzyme systems, including Nox, xanthine oxidase, endothelial nitric oxide synthase, lipoxygenases, and myeloperoxidase . Scioli et al reported that propionyl‐L‐carnitine reduced Nox‐mediated oxidative stress and improved rat skin flap viability . The present study showed that NO‐NIF decreased p22phox protein expression.…”

“…Actually, use of superoxide dismutase (SOD), an endogenous scavenger of the superoxide radical, increased flap survival . Other antioxidative drugs have also successfully been applied to protect against flap necrosis in animal models …”

“…1,2 Other antioxidative drugs have also successfully been applied to protect against flap necrosis in animal models. [10][11][12][13][14][15] Nitrosonifedipine [2,6-dimethyl-4-(2-nitrosophenyl)23,5pyridinedicarboxylic acid dimethyl ester] (NO-NIF) is a nitroso analog of nifedipine which is an L-type Ca2 1 -channel blocker. NO-NIF is highly reactive to lipid-derived radicals in vitro, and participates in ROS radical scavenging activity at the cell membrane.…”

Effect of Topical Administration of Fractions and Isolated Molecules from Plant Extracts on Skin Wound Healing: A Systematic Review of Murine Experimental Models

“…It is already known that the oxidative stress induces cell damage, lipid, protein, and nucleic acids oxidation [66, 67]. It is recognized that cutaneous trauma increases the tissue oxidative stress in the wounded area [66–69]. Although reactive species are able to activate cell signaling pathways and stimulate cell proliferation, differentiation, and neoangiogenesis, excessive production of these molecules inhibits the healing process, especially by inducing cell death and molecular damage in the extracellular matrix [23, 70, 71].…”

“…However, from all analyzed studies, only 15% investigated the oxidative status. This is a surprising finding, since the antioxidant effect is a pivotal mechanism indicated in several studies to support the applicability of plant extracts in the treatment of tissue damage, including skin wounds [66–69]. Another fundamental result on the cutaneous repair process is the restoration of the biomechanical properties, especially the tensile force of the newly formed tissue, which provides functional estimates on the quality of the healing process [37].…”