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

Scioli MG, Lo Giudice P, Bielli A, Tarallo V, De Rosa A, De Falco S, Orlandi A - PLoS ONE (2015)

Bottom Line: 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.Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction.The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy.

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.

Methods and 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

PLC accelerates experimental wound healing in vitro.(A) In vitro wound healing assay in HMVEC monolayers with or without PLC treatment (1mM) at time 0 (T0) and after 16 hours (T16). (B) Bar graph showing an increased percentage of scratch closure in PLC-treated HMVEC monolayers. Magnification 4X. t-Student: * indicates p< 0.05. Values are expressed as mean ± SEM of three separate experiments.
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pone.0140697.g004: PLC accelerates experimental wound healing in vitro.(A) In vitro wound healing assay in HMVEC monolayers with or without PLC treatment (1mM) at time 0 (T0) and after 16 hours (T16). (B) Bar graph showing an increased percentage of scratch closure in PLC-treated HMVEC monolayers. Magnification 4X. t-Student: * indicates p< 0.05. Values are expressed as mean ± SEM of three separate experiments.

Mentions: In PLC-treated rats, skin wounds re-epithelialized faster compared with vehicle (Fig 2) and this effect was dose-dependent. Representative microphotographs and microscopic evaluation of granulation tissue of rat skin wounds 7 days after wound are reported in Fig 3. Wounds in the upper region of both vehicle and PLC-120 treated rats showed a granulation tissue with dense CD31+ microvasculature (p< 0.01; Fig 3). Histomorphometric analysis documented that the percentage and signal intensity of VEGF+ microvessels were both increased in PLC-treated rats compared with vehicle tissue (p< 0.01 and p< 0.001, respectively); although the percentage of PlGF+ microvessels did not change, an increase of signal intensity was detected in PLC-treated rats (p< 0.05). Finally, PLC-treated rats showed an increase in the percentage and immunoreactivity of iNOS+ microvessels compared with vehicle (p< 0.05 and p< 0.01, respectively), whereas Nox4+ microvessels and signal intensity were reduced in PLC-treated rats (p< 0.05). Finally, as reported in Fig 4, in vitro wound healing assay showed that the percentage of scratch closure was higher in PLC-treated than in vehicle HMVEC monolayers (p< 0.05).


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

Scioli MG, Lo Giudice P, Bielli A, Tarallo V, De Rosa A, De Falco S, Orlandi A - PLoS ONE (2015)

PLC accelerates experimental wound healing in vitro.(A) In vitro wound healing assay in HMVEC monolayers with or without PLC treatment (1mM) at time 0 (T0) and after 16 hours (T16). (B) Bar graph showing an increased percentage of scratch closure in PLC-treated HMVEC monolayers. Magnification 4X. t-Student: * indicates p< 0.05. Values are expressed as mean ± SEM of three separate experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608702&req=5

pone.0140697.g004: PLC accelerates experimental wound healing in vitro.(A) In vitro wound healing assay in HMVEC monolayers with or without PLC treatment (1mM) at time 0 (T0) and after 16 hours (T16). (B) Bar graph showing an increased percentage of scratch closure in PLC-treated HMVEC monolayers. Magnification 4X. t-Student: * indicates p< 0.05. Values are expressed as mean ± SEM of three separate experiments.
Mentions: In PLC-treated rats, skin wounds re-epithelialized faster compared with vehicle (Fig 2) and this effect was dose-dependent. Representative microphotographs and microscopic evaluation of granulation tissue of rat skin wounds 7 days after wound are reported in Fig 3. Wounds in the upper region of both vehicle and PLC-120 treated rats showed a granulation tissue with dense CD31+ microvasculature (p< 0.01; Fig 3). Histomorphometric analysis documented that the percentage and signal intensity of VEGF+ microvessels were both increased in PLC-treated rats compared with vehicle tissue (p< 0.01 and p< 0.001, respectively); although the percentage of PlGF+ microvessels did not change, an increase of signal intensity was detected in PLC-treated rats (p< 0.05). Finally, PLC-treated rats showed an increase in the percentage and immunoreactivity of iNOS+ microvessels compared with vehicle (p< 0.05 and p< 0.01, respectively), whereas Nox4+ microvessels and signal intensity were reduced in PLC-treated rats (p< 0.05). Finally, as reported in Fig 4, in vitro wound healing assay showed that the percentage of scratch closure was higher in PLC-treated than in vehicle HMVEC monolayers (p< 0.05).

Bottom Line: 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.Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction.The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine and Prevention, Anatomic Pathology, University of Tor Vergata, Rome, Italy.

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.

Methods and 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus