title: Propionyl-L-carnitine reduces proliferation and potentiates Bax-related apoptosis of aortic intimal smooth muscle cells by modulating nuclear factor-kappaB activity.
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.
authors.affiliation: Institute of Anatomic Pathology, Tor Vergata University, Rome 00133, Italy and. Electronic address: orlandi@uniroma2.it.
authors.forename: Augusto
authors.initials: A
authors.lastname: Orlandi
authors.affiliation: Institute of Anatomic Pathology, Tor Vergata University, Rome 00133, Italy and.
authors.forename: Arianna
authors.initials: A
authors.lastname: Francesconi
authors.affiliation: Sigma-Tau Research Laboratories, Pomezia (Rome) 00040, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Marcellini
authors.affiliation: Institute of Anatomic Pathology, Tor Vergata University, Rome 00133, Italy and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Lascio
authors.affiliation: Institute of Anatomic Pathology, Tor Vergata University, Rome 00133, Italy and.
authors.forename: Luigi Giusto
authors.initials: LG
authors.lastname: Spagnoli
mesh_terms: D000818:Animals; D001011:Aorta / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D016196:S Phase / Q000187:drug effects*; D017539:Tunica Intima / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C494828:Bax protein, rat; D002316:Cardiotonic Agents; D009124:Muscle Proteins; D016328:NF-kappa B; D051028:bcl-2-Associated X Protein; C003223:propionylcarnitine; D002331:Carnitine