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

• Published in: Biological & pharmaceutical bulletin Vol. 34; no. 8; pp. 1204 - 1214
• Main Authors: Scagliarini, Alessandra, Lavitrano, Marialuisa, Cerrito, Maria Grazia, Liloia, Angela, Mainetti, Lara, Giovannoni, Roberto, Villa, Matteo, Bach, Fritz Heintz, Busnelli, Marco, Froio, Alberto, Leone, Biagio Eugenio, Otterbein, Leo Edmond, Biasi, Giorgio Maria
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.08.2011; Japan Science and Technology Agency
• Subjects: Animals; Apoptosis; Caspase 3 - metabolism; Cell Proliferation; Disease Models, Animal; Gene Expression; heme oxygenase-1; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - genetics; Hyperplasia - prevention & control; intimal hyperplasia; Male; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - injuries; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - therapeutic use; Nitric Oxide Synthase Type II - metabolism; proliferation; Rats; Rats, Sprague-Dawley; Tunica Intima - metabolism; Tunica Intima - pathology; X-Linked Inhibitor of Apoptosis Protein - metabolism
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.34.1204

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.