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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 ameliorates mitochondrial β-oxidation in serum-deprived HMVECs.(A) FAD level (β-oxidation impairment) measured as optical density (OD) assay in basal condition (5% FBS) and serum-deprived HMVECs treated with PBS (vehicle, 12h), L-aminocarnitine (L-amino, 1μM, 12h) and/or PLC (1mM, 12h). (B) ROS level detection by dichlorodihydrofluorescein fluorescence intensity (DCF, F.I) assay in treated cells. (C) Real-time PCR for Nox4 transcripts in treated cells. (D) Leukocyte adhesion evaluation in treated cells. Data are shown as mean ± SEM. Student’s t-test: *, ** and *** indicate p< 0.05; p< 0.01 and p< 0.001. Abbreviations: OD, optical density; HPF, high power field.
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pone.0140697.g008: PLC ameliorates mitochondrial β-oxidation in serum-deprived HMVECs.(A) FAD level (β-oxidation impairment) measured as optical density (OD) assay in basal condition (5% FBS) and serum-deprived HMVECs treated with PBS (vehicle, 12h), L-aminocarnitine (L-amino, 1μM, 12h) and/or PLC (1mM, 12h). (B) ROS level detection by dichlorodihydrofluorescein fluorescence intensity (DCF, F.I) assay in treated cells. (C) Real-time PCR for Nox4 transcripts in treated cells. (D) Leukocyte adhesion evaluation in treated cells. Data are shown as mean ± SEM. Student’s t-test: *, ** and *** indicate p< 0.05; p< 0.01 and p< 0.001. Abbreviations: OD, optical density; HPF, high power field.

Mentions: Since PLC has a specific role in the transport of fatty acids into the mitochondria [22], we investigated if β-oxidation is the pharmacological target of PLC and its regulation is involved in the endothelial oxidative stress using the specific inhibitor L-aminocarnitine [42]. As shown in Fig 8, in HMVEC cultures L-aminocarnitine induced the impairment of β-oxidation as documented by the increase of FAD level, ROS generation and Nox4 expression, as well as leukocyte adhesion (p< 0.001). Interestingly, the adding of L-aminocarnitine counteracted the antioxidant effect of PLC in serum-deprived HMVECs (p< 0.05), strongly supporting that the pharmacological target of PLC is the mitochondrial β-oxidation, that is in turn involved in Nox4-dependent oxidative stress.


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 ameliorates mitochondrial β-oxidation in serum-deprived HMVECs.(A) FAD level (β-oxidation impairment) measured as optical density (OD) assay in basal condition (5% FBS) and serum-deprived HMVECs treated with PBS (vehicle, 12h), L-aminocarnitine (L-amino, 1μM, 12h) and/or PLC (1mM, 12h). (B) ROS level detection by dichlorodihydrofluorescein fluorescence intensity (DCF, F.I) assay in treated cells. (C) Real-time PCR for Nox4 transcripts in treated cells. (D) Leukocyte adhesion evaluation in treated cells. Data are shown as mean ± SEM. Student’s t-test: *, ** and *** indicate p< 0.05; p< 0.01 and p< 0.001. Abbreviations: OD, optical density; HPF, high power field.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140697.g008: PLC ameliorates mitochondrial β-oxidation in serum-deprived HMVECs.(A) FAD level (β-oxidation impairment) measured as optical density (OD) assay in basal condition (5% FBS) and serum-deprived HMVECs treated with PBS (vehicle, 12h), L-aminocarnitine (L-amino, 1μM, 12h) and/or PLC (1mM, 12h). (B) ROS level detection by dichlorodihydrofluorescein fluorescence intensity (DCF, F.I) assay in treated cells. (C) Real-time PCR for Nox4 transcripts in treated cells. (D) Leukocyte adhesion evaluation in treated cells. Data are shown as mean ± SEM. Student’s t-test: *, ** and *** indicate p< 0.05; p< 0.01 and p< 0.001. Abbreviations: OD, optical density; HPF, high power field.
Mentions: Since PLC has a specific role in the transport of fatty acids into the mitochondria [22], we investigated if β-oxidation is the pharmacological target of PLC and its regulation is involved in the endothelial oxidative stress using the specific inhibitor L-aminocarnitine [42]. As shown in Fig 8, in HMVEC cultures L-aminocarnitine induced the impairment of β-oxidation as documented by the increase of FAD level, ROS generation and Nox4 expression, as well as leukocyte adhesion (p< 0.001). Interestingly, the adding of L-aminocarnitine counteracted the antioxidant effect of PLC in serum-deprived HMVECs (p< 0.05), strongly supporting that the pharmacological target of PLC is the mitochondrial β-oxidation, that is in turn involved in Nox4-dependent oxidative stress.

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