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J. Biol. Chem., Vol. 282, Issue 7, 4932-4942, February 16, 2007

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Propionyl-L-carnitine Reduces Proliferation and Potentiates Bax-related Apoptosis of Aortic Intimal Smooth Muscle Cells by Modulating Nuclear Factor-B Activity^*

Augusto Orlandi¹, Arianna Francesconi, Marcella Marcellini, Antonio Di Lascio, and Luigi Giusto Spagnoli

From the Institute of Anatomic Pathology, Tor Vergata University, Rome 00133, Italy and Sigma-Tau Research Laboratories, Pomezia (Rome) 00040, Italy

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-B 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-B, 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 G₁ 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-B 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-B activity in intimal cells was also due to the increase of IB- bioavailability, as the result of a parallel induction of IB- synthesis and reduction of phosphorylation and degradation. Collectively, these findings document that NF-B activity inhibition contributes to PLC-induced proliferative arrest and Bax-related apoptosis of intimal SMCs.

Received for publication, June 27, 2006 , and in revised form, November 22, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the Gen-Bank^TM/EBI Data Bank with accession number(s) NM_023987 [GenBank] , AF_190020, X63722 [GenBank] , NM_031530 [GenBank] , X02231 [GenBank] , XM_343065 [GenBank] , NM_199267 [GenBank] , and XM_342346 [GenBank] .

^* This study was supported in part by a grant from Spedali Civili of Brescia (Protocol 20906055) and Sigma Tau (Pomezia) for animal maintenance. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Anatomic Pathology Institute, Dept. Biopathology and Image Diagnostics, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy. Tel.: 39-06-20903960; Fax: 39-06-20902209; E-mail: orlandi{at}uniroma2.it.

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