Heme Oxygenase-1 Inhibition Prevents Intimal Hyperplasia Enhancing Nitric Oxide-Dependent Apoptosis of Vascular Smooth Muscle Cells

作者：Cerrito Maria Grazia; Scagliarini Alessandra; Froio Alberto; Liloia Angela; Busnelli Marco; Giovannoni Roberto; Otterbein Leo Edmond; Mainetti Lara; Villa Matteo; Bach Fritz Heintz; Leone Biagio Eugenio; Biasi Giorgio Maria; Lavitrano Marialuisa^*

来源：Biological & Pharmaceutical Bulletin, 2011, 34(8): 1204-1214.

DOI：10.1248/bpb.34.1204

• nitric oxide
• heme oxygenase-1
• proliferation
• apoptosis
• intimal hyperplasia

Heme oxygenase-1 (HO-1, encoded by the HMOX1 gene) and inducible nitric oxide synthase (iNOS) have been implicated in vascular disease; however the role of these genes remains unclear. Therefore, we studied the mechanism by which iNOS-derived nitric oxide (NO) affects the intimal hyperplasia (IH) formation in relation to HO-1. We show, in a model of balloon injury in rats, that the suppression of vascular smooth muscle cells (VSMC) proliferation by NO required HO-1, while induction of apoptosis of the VSMC by NO does not involve HO-1. To better clarify the molecular mechanism of this finding, we used Hmox1(+/+) and Hmox1(-/-) VSMC exposed to NO. In Hmox1(+/+) VSMC, NO is antiproliferative (up to 34% inhibition) and it is associated to an increase of apoptosis (up to 35%) due to a decrease of X-linked inhibitor of apoptosis protein (XIAP) expression level and to the activation of caspase-3. In the absence of HO-1 (Hmox1(-/-) VSMC) apoptosis was significantly greater (69% p<0.01 vs. Hmox1(+/+) VSMC) demonstrating that HO-1 attenuated the pro-apoptotic effect of NO on VSMC. In the context of IH, the pro-apoptotic effect of NO on VSMC is increased in the absence of HO-1 and exerts therapeutic effects with a significant reduction in IH.

• 出版日期2011-8