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.
Highlights
Physiological wound healing is a highly organized dynamic process requiring tight temporal and spatial coordination of various events and signaling networks aimed to provide a protective barrier against further external stimuli or infections [1,2]
We investigated the effects of PLC in rat skin flap and cutaneous wound healing
Dermal microvascular endothelial cell dysfunction was prevented by NADPH-oxidase 4 (Nox4) inhibition
Summary
Physiological wound healing is a highly organized dynamic process requiring tight temporal and spatial coordination of various events and signaling networks aimed to provide a protective barrier against further external stimuli or infections [1,2]. Endothelial dysfunction contributes to microangiopathy that impairs cutaneous microvascular blood flow, hypoxia and accelerated inflammation, causing delayed healing or chronic wounds [4,5]. Reduction in cutaneous blood flow, oxygen tension, abnormal angiogenesis and increased levels of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) further support the hypothesis that endothelial cell dysfunction is responsible for impaired wound repair [3]. ROS are produced by several enzyme systems, including NADPH oxidase (Nox), xanthine oxidase, endothelial nitric oxide synthase, lipoxygenases and myeloperoxidase [10]. 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
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