Propionyl- l -Carnitine Improves Postischemic Blood Flow Recovery and Arteriogenetic Revascularization and Reduces Endothelial NADPH-Oxidase 4–Mediated Superoxide Production

Abstract

Objective-The beneficial effect of the natural compound propionyl-L-carnitine (PLC) on intermittent claudication in patients with peripheral arterial disease is attributed to its anaplerotic function in ischemic tissues, but inadequate information is available concerning action on the vasculature. Methods and Results-We investigated the effects of PLC in rabbit hind limb collateral vessels after femoral artery excision, mouse dorsal air pouch, chicken chorioallantoic membrane, and vascular cells by angiographic, Doppler flow, and histomorphometrical and biomolecular analyses. PLC injection accelerated hind limb blood flow recovery after 4 days (PϽ0.05) and increased angiographic quadriceps collateral vascularization after 7 days (PϽ0.001) Histomorphometry confirmed the increased vascular area (PϽ0.05), with unchanged intramuscular capillary density. PLCinduced dilatative adaptation, and growth was found associated with increased inducible nitric oxide synthase and reduced arterial vascular endothelial growth factor and intracellular adhesion molecule-1 expression. PLC also increased vascularization in air pouch and chorioallantoic membrane (PϽ0.05), particularly in large vessels. PLC increased endothelial and human umbilical vascular endothelial cell proliferation and rapidly reduced inducible nitric oxide synthase and NADPH-oxidase 4 -mediated reactive oxygen species production in human umbilical vascular endothelial cells; NADPH-oxidase 4 also regulated NF-B-independent intracellular adhesion molecule-1 expression. Conclusion-Our results provided strong evidence that PLC improves postischemic flow recovery and revascularization and reduces endothelial NADPH-oxidase-related superoxide production. We recommend that PLC should be included among therapeutic interventions that target endothelial function. Key Words: arteriogenesis Ⅲ endothelial function Ⅲ oxidative stress Ⅲ vascular function P eripheral arterial disease (PAD) is the most common clinical consequence of atherosclerosis, affecting Ϸ20% of adults older than age 55 years. 1 Atherosclerotic occlusion of leg arteries induces clinical manifestations, most frequently intermittent claudication. 1,2 Among the functional vascular changes observed with atherosclerosis, endothelial dysfunction plays a major role. 3,4 L-carnitine is a natural amino acid that plays a crucial role in the shuttle mechanism of long-chain fatty acids and in fueling ␤ oxidation. 5 The endogenous L-carnitine pool includes a series of short-chain, medium-chain, and long-chain esters in homeostatic equilibrium. 5,6 Propionyl-L-carnitine (PLC) is a short-chain L-carnitine ester that has been introduced among emerging noninterventional medical regiments that aim to counteract PAD-related adverse effects. 1,2,7 PLC activity is classically related to the anaplerotic function of providing substrates for energy expenditure in ischemic tissues. 1,8 Although some data showed beneficial remodeling after injury, 9 the mechanisms through which PLC influences arterial function remain largely hypot...

Effects of <smlcap>L</smlcap>-Carnitine on High Glucose-Induced Oxidative Stress in Retinal Ganglion Cells

“…ROS are highly reactive and can initiate reactions that can lead to irreversible damage to proteins or lipids, causing cellular dysfunction and cytotoxicity. More recently, propionyl- L -carnitine administration has been shown to decrease the expression of the ROS-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase [33]. Although the link between this carnitine ester and protein expression has not been clarified, the decrease in ROS formation appears to underlie the improvement in postischemic flow recovery and revascularization induced by propionyl- L -carnitine.…”

Antioxidant Treatment Prevents Serum Deprivation- and TNF-α-Induced Endothelial Dysfunction through the Inhibition of NADPH Oxidase 4 and the Restoration of β-Oxidation

“…ROS levels in HUVECs were measured by 5-(and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H 2 DCFDA) fluorescence method (Molecular Probes, Inc., Eugene, Oreg., USA), as described previously [16]. Fluorescence was monitored by analyzing at least 10,000 cells using a flow cytometer (Beckman Coulter, Brea, Calif., USA).…”

“…ROS can be produced by several enzyme systems, including NADPH oxidase (Nox), xanthine oxidase, endothelial nitric oxide synthase, lipoxygenases and myeloperoxidase [14]. Although all those enzymes can potentially contribute to the oxidative stress, Nox isoforms are the predominant source of ROS in the vasculature and Nox4 is the major endothelial isoform [15,16]. Under inflammatory stimulation, the activated endothelium displays an increased expression of cell adhesion molecules (CAMs), such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and inflammatory cytokine secretion, such as macrophage/monocyte chemoattractant protein-1 (MCP-1) [17,18].…”

“…PLC was also documented to be an antioxidant agent, protecting tissues from oxidative damage. In particular, PLC has been documented to be capable of reducing membrane lipid peroxidation and the effects of hypoxia in cardiomyocytes [27], endothelial dysfunction in ischemic rabbit limbs [16] and in human inflammatory bowel diseases [28]. In spite of their various employments in clinical practice, the molecular basis of the therapeutic efficacy of antioxidants remains largely unexplored.…”

Adipose Tissue-Derived Stem Cell Therapy for Post-Surgical Breast Reconstruction - More Light than Shadows

“…In response to damage or ischemia, circulating and resident stem cells promote angiogenesis through secretion of growth factor, such as VEGF, while collagen synthesis contributes to tissue remodelling following acute and chronic damages [11][12][13]. Actually, major attention has been focused in order to clarify if the transfer of ASCs-containing SVF may increase the risk of breast cancer development or relapse [14].…”