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

Published on Oct 16, 2015in PLOS ONE2.74
· DOI :10.1371/JOURNAL.PONE.0140697
Maria Giovanna Scioli26
Estimated H-index: 26
,
Pietro Lo Giudice10
Estimated H-index: 10
(Sigma-Tau)
+ 4 AuthorsAugusto Orlandi54
Estimated H-index: 54
Sources
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.
Figures & Tables
Download
📖 Papers frequently viewed together
21 Citations
2 Citations
101 Citations
References69
Newest
#1Maria Giovanna Scioli (Prevention Institute)H-Index: 26
#1Maria Giovanna Scioli (Prevention Institute)H-Index: 1
Last. Augusto Orlandi (Prevention Institute)H-Index: 54
view all 5 authors...
A decline in the function of the microvasculature occurs with ageing. An impairment of endothelial properties represents a main aspect of age-related microvascular alterations. Endothelial dysfunction manifests itself through a reduced angiogenic capacity, an aberrant expression of adhesion molecules and an impaired vasodilatory function. Increased expression of adhesion molecules amplifies the interaction with circulating factors and inflammatory cells. The latter occurs in both conduit arterie...
51 CitationsSource
#1Anna Konior (Jagiellonian University)H-Index: 6
#2Agata SchrammH-Index: 3
Last. Tomasz J. GuzikH-Index: 67
view all 4 authors...
Abstract Significance: Reactive oxygen species (ROS) play a critical role in vascular disease. While there are many possible sources of ROS, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases play a central role. They are a source of “kindling radicals,” which affect other enzymes, such as nitric oxide synthase endothelial nitric oxide synthase or xanthine oxidase. This is important, as risk factors for atherosclerosis (hypertension, diabetes, hypercholesterolemia, and smoking) regulat...
264 CitationsSource
Propionyl- L -Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature
24 CitationsSource
In this study, a sterile and biocompatible chitosan (CHI) gel for wound healing applications was formulated. CHI powder was treated in autoclave (ttCHI) to prepare sterile formulations. The heat treatment modified the CHI molecular weight, as evidenced by GPC analysis, and its physical–chemical features. Differential scanning calorimetry studies indicated that the macromolecules, before and after thermal treatment, differ in the strength of water-polymer interaction leading to different viscoela...
24 CitationsSource
#1Elizabeth WhitlockH-Index: 1
#2Jenny MorcomH-Index: 2
Last. Seamus RyanH-Index: 1
view all 5 authors...
The management of wounds presents a significant burden to healthcare services, consuming a large amount of human and financial resources. According to the Australian Wound Management Association, an estimated 400000 Australians have a chronic wound or ulcer at any given time. This high incidence of chronic wounds translates into a major burden on the healthcare system and annual costs were estimated to be $3 billion in 2005.
15 Citations
#1Jing Dong (Fudan University)H-Index: 4
#2Mingjun Cheng (Fudan University)H-Index: 1
Last. Hong Sun (Fudan University)H-Index: 5
view all 3 authors...
: Inducible nitric oxide synthase (iNOS) is the key enzyme in NO synthesis and exhibits a high expression in numerous types of malignant tumors. Previous studies have demonstrated that iNOS promotes the production of tumor blood vessels by catalyzing the synthesis of additional NO. Certain experimental evidence has suggested that iNOS may regulate the levels of vascular endothelial growth factor (VEGF), as the level of VEGF may be induced by iNOS during endothelial cell migration and angiogenesi...
16 CitationsSource
#1Graziela S. Ribas (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 13
#2Carmen Regla Vargas (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 32
Last. Moacir Wajner (UFRGS: Universidade Federal do Rio Grande do Sul)H-Index: 67
view all 3 authors...
Abstract In recent years increasing evidence has emerged suggesting that oxidative stress is involved in the pathophysiology of a number of inherited metabolic disorders. However the clinical use of classical antioxidants in these diseases has been poorly evaluated and so far no benefit has been demonstrated. l -Carnitine is an endogenous substance that acts as a carrier for fatty acids across the inner mitochondrial membrane necessary for subsequent beta-oxidation and ATP production. Besides it...
118 CitationsSource
#1Maria Giovanna Scioli (University of Rome Tor Vergata)H-Index: 26
#2Alessandra BielliH-Index: 16
Last. Augusto OrlandiH-Index: 54
view all 9 authors...
Aims: Oxidative stress plays a pivotal role in the impaired endothelial function occurring in vascular diseases. Antioxidant strategies induce a clinical advantage in patients with endothelial dysfunction and atherosclerosis and protect from oxidative damage, but the underlying molecular mechanisms have been poorly evaluated. The aim of this study was to analyze the effects and mechanisms of action of antioxidant regimens on endothelial function. Methods and Results: Antioxidant efficacy of N-ac...
21 CitationsSource
#1James M. May (Vandy: Vanderbilt University)H-Index: 58
#2Fiona E. HarrisonH-Index: 25
Abstract Significance: Vitamin C, or ascorbic acid, has long been known to participate in several important functions in the vascular bed in support of endothelial cells. These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis, scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow. Although ascorbate may not be able to reverse infla...
137 CitationsSource
#1Eric P. Brass (UCLA: University of California, Los Angeles)H-Index: 56
#2David KosterH-Index: 1
Last. Antonino Amato (Sigma-Tau)H-Index: 19
view all 4 authors...
Propionyl-l-carnitine (PLC) may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for ...
21 CitationsSource
Cited By12
Newest
Inflammatory bowel diseases (IBD) are a group of chronic, incurable diseases of the digestive tract, the etiology of which remains unclear to this day. IBD result in significant repercussions on the quality of patients’ life. There is a continuous increase in the incidence and prevalence of IBD worldwide, and it is becoming a significant public health burden. Pharmaceuticals commonly used in IBD management, for example, mesalamine, sulfasalazine, corticosteroids, and others, expose patients to d...
Source
#1Remzi Dogan (Bezmialem Foundation University)H-Index: 11
#2Eray Metin Guler (Bezmialem Foundation University)H-Index: 10
Last. Orhan Ozturan (Bezmialem Foundation University)H-Index: 24
view all 8 authors...
ABSTRACT Objective The aim of this study was to compare the efficacy of multiple antioxidant (Proxeed Plus (PP) with Carnitine, Selenium, Zinc, Coenzyme Q10, Vitamin C, Folic Acid, Vitamin B12) on local random skin flap healing with the hyperbaric oxygen (HBO) therapy. Methods Fourty rats were equally divided into five groups (Control, PP, HBO, HBO+PP, PP+HBO+PP). Local random McFarlane skin flap was applied to all rats. Following the applications, evaluations were made biochemical (TAS, TOS, OS...
Source
#1Ulaş Bali (Celal Bayar University)H-Index: 2
#2Işıl AydemirH-Index: 4
Last. Mehmet İbrahim Tuğlu (Celal Bayar University)H-Index: 7
view all 5 authors...
We investigated lateral thoracic and posterior thigh perforator flaps for viability, vascularization, perfusion and apoptosis in a rat model. Wistar albino rats were divided into six groups: latera...
Source
#1Li Li (MOE: Chinese Ministry of Education)H-Index: 1
#2Muyan Chen (MOE: Chinese Ministry of Education)H-Index: 2
Last. Kenneth B. Storey (Carleton University)H-Index: 90
view all 3 authors...
Abstract Hypoxia is a severe problem in aquatic environments worldwide and has caused mass mortality of sea cucumbers (& other species) for decades, seriously affecting the sustainable development of aquaculture. Investigations of the metabolic disruptions and biochemical responses associated with acute hypoxia stress in sea cucumbers can provide a theoretical basis and guidance for improving aquaculture. A metabolomics approach to characterize changes in the profiles of endogenous small molecul...
8 CitationsSource
#1Hui Jin (Guangzhou Medical University)H-Index: 7
#1Hui Jin (Guangzhou Medical University)H-Index: 1
Last. Lei SuH-Index: 1
view all 7 authors...
This study was conducted to explore underlying mechanism of microcirculation dysfunction and protectiverole of Xuebijing in heat stroke. Forty rats were divided into: control, vehicle + heat stress (HS), superoxide dismutase (SOD) + HS, and Xuebijing + HS groups. Rats in heat stress groups were subjected to continuous heat stress in infant incubator 1 h after tail vein injection of the tested compound and spinotrapezius preparation. Velocity of blood flow through micro-vessels and vascular diame...
7 CitationsSource
#1Karin van Veldhoven (Imperial College London)H-Index: 14
#2Pekka Keski-Rahkonen (IARC: International Agency for Research on Cancer)H-Index: 24
Last. Manolis KogevinasH-Index: 104
view all 15 authors...
Abstract Background Exposure to disinfection by-products (DBPs) in drinking water and chlorinated swimming pools are associated with adverse health outcomes, but biological mechanisms remain poorly understood. Objectives Evaluate short-term changes in metabolic profiles in response to DBP exposure while swimming in a chlorinated pool. Materials and methods The PISCINA-II study (EXPOsOMICS project) includes 60 volunteers swimming 40 min in an indoor pool. Levels of most common DBPs were measured ...
32 CitationsSource
#1Yutaka FukunagaH-Index: 1
#2Yuki Izawa-IshizawaH-Index: 16
Last. Toshiaki Tamaki (University of Tokushima)H-Index: 48
view all 10 authors...
Ischemic skin flap necrosis can occur in random pattern flaps. An excess amount of reactive oxygen species is generated and causes necrosis in the ischemic tissue. Nitrosonifedipine (NO-NIF) has been demonstrated to possess potent radical scavenging ability. However, there has been no study on the effects of NO-NIF on ischemic skin flap necrosis. Therefore, they evaluated the potential of NO-NIF in ameliorating ischemic skin flap necrosis in a mouse model. A random pattern skin flap (1.0 × 3.0 c...
6 CitationsSource
#1Xue HanH-Index: 5
#2Ya-Ping DengH-Index: 8
Last. Guo-Jun JiangH-Index: 8
view all 8 authors...
Refractory wound is a dreaded complication of diabetes and is highly correlated with EPC dysfunction caused by hyperglycemia. Acarbose is a widely used oral glucose-lowering drug exclusively for T2DM. Previous studies have suggested the beneficial effect of acarbose on improving endothelial dysfunction in patients with T2DM. However, no data have been reported on the beneficial efficacy of acarbose in wound healing impairment caused by diabetes. We herein investigated whether acarbose could impr...
8 CitationsSource
#1Pietro Gentile (University of Rome Tor Vergata)H-Index: 36
#2John P. ColeH-Index: 3
Last. Valerio Cervelli (University of Rome Tor Vergata)H-Index: 43
view all 9 authors...
Platelet rich plasma (PRP) was tested as a potential therapy for androgenetic alopecia (AGA) through two different clinical protocols in which one population (18 participants) received half-head treatment with autologous non-activated PRP (A-PRP) produced by CPunT Preparation System (Biomed Device, Modena, Italy) and the other half-head with placebo, and a second separated population in which all participants (n = 6, 3 participants per group) received treatment with calcium-activated PRP (AA-PRP...
65 CitationsSource
Background and Purpose. Skin wound healing is a dynamic process driven by molecular events responsible for the morphofunctional repair of the injured tissue. In a systematic review, we analyzed the relevance of plant fractions and isolates on skin wound healing. By revising preclinical investigations with murine models, we investigated if the current evidence could support clinical trials. Methods. Studies were selected in the MEDLINE/PubMed and Scopus databases according to the PRISMA statement...
2 CitationsSource