1. Propionyl-L-carnitine Reduces Proliferation and Potentiates Bax-related Apoptosis of Aortic Intimal Smooth Muscle Cells by Modulating Nuclear Factor-κB Activity
- Author
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Arianna Francesconi, Luigi Giusto Spagnoli, Antonio Di Lascio, Marcella Marcellini, and Augusto Orlandi
- Subjects
Male ,Vascular smooth muscle ,Wistar ,protein p50 ,Apoptosis ,Biological organs ,Enzyme activity ,Enzyme inhibition ,Muscle ,Nucleotides ,Cell apoptosis ,Propionyl-L-carnitine (PLC) ,Rabbits ,Smooth muscle cells (SMC) ,Cell death ,antisense oligodeoxynucleotide ,cytochrome c ,I kappa B alpha ,immunoglobulin enhancer binding protein ,inhibitor of apoptosis protein 1 ,inhibitor of apoptosis protein 2 ,monocyte chemotactic protein 1 ,propionylcarnitine ,protein Bax ,protein bcl 2 ,sn 50 ,survivin ,synaptotagmin I ,vascular cell adhesion molecule 1 ,Bax protein, rat ,cardiotonic agent ,carnitine ,drug derivative ,muscle protein ,animal cell ,animal experiment ,animal model ,animal tissue ,aorta intima ,apoptosis ,artery injury ,artery intima proliferation ,article ,bioavailability ,cell culture ,cell cycle arrest ,cell cycle G1 phase ,cell cycle S phase ,cell proliferation ,comparative study ,controlled study ,dose response ,drug mechanism ,enzyme activity ,enzyme inhibition ,in vivo study ,male ,modulation ,nonhuman ,nucleotide sequence ,priority journal ,protein degradation ,protein expression ,protein phosphorylation ,protein secretion ,rat ,serum ,smooth muscle fiber ,upregulation ,animal ,aorta ,drug effect ,injury ,intima ,metabolism ,molecular genetics ,pathology ,rabbit ,Wistar rat ,Oryctolagus cuniculus ,Rattus ,Animals ,Aorta ,Base Sequence ,bcl-2-Associated X Protein ,Cardiotonic Agents ,Carnitine ,Dose-Response Relationship, Drug ,G1 Phase ,Molecular Sequence Data ,Muscle Proteins ,Myocytes, Smooth Muscle ,NF-kappa B ,Rats ,Rats, Wistar ,S Phase ,Tunica Intima ,Up-Regulation ,Biochemistry ,Smooth Muscle ,Cytochrome c ,Settore MED/08 - Anatomia Patologica ,Dose-Response Relationship ,In vivo ,Survivin ,Cell adhesion ,Molecular Biology ,Myocytes ,Immunology ,biology ,medicine.anatomical_structure ,Drug ,Bax protein ,P50 ,medicine ,Monocyte ,Cell Biology ,Cancer research ,biology.protein - Abstract
Propionyl-l-carnitine (PLC) has been introduced among the therapeutic approaches of peripheral arterial disease, and more recently, an increase of intimal cell apoptosis has been demonstrated to contribute to its effectiveness in rabbit carotid postinjury myointimal hyperplasia prevention. How PLC mediates these effects on vascular smooth muscle cells (SMCs) remains poorly understood. We investigated the role of NF-kappaB in PLC-induced arterial remodeling. In vivo, daily PLC treatment 15 days after injury resulted in a reduction of relative rat aortic intimal volume, an increase of apoptosis, Bax up-regulation without changing the Bcl-2 level, and a reduction of NF-kappaB, vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and survivin in myointimal thickening compared with controls. In the presence of 10% serum, a reduced G(1) --S phase progression preceded PLC-induced intimal cell apoptosis; in 0.1% serum cultures, in a dose-dependent manner, PLC rapidly induced intimal cell apoptosis and reduced p65, p50, IAP-1, and IAP-2 expression. Inhibiting NF-kappaB activation through SN50 increased apoptotic rate and Bax expression in intimal but not in medial SMCs, and successive PLC treatment failed to induce a further increase in apoptotic rate. Bax antisense oligodeoxynucleotide reduced PLC-induced intimal cell apoptosis and cytochrome c release. The PLC-induced attenuation of NF-kappaB activity in intimal cells was also due to the increase of IkappaB-alpha bioavailability, as the result of a parallel induction of IkappaB-alpha synthesis and reduction of phosphorylation and degradation. Collectively, these findings document that NF-kappaB activity inhibition contributes to PLC-induced proliferative arrest and Bax-related apoptosis of intimal SMCs.
- Published
- 2007