title: Heme oxygenase-1 inhibition prevents intimal hyperplasia enhancing nitric oxide-dependent apoptosis of vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Molecular Medicine Laboratory, University of Milano-Bicocca, Monza, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cerrito
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scagliarini
authors.forename: Alberto
authors.initials: A
authors.lastname: Froio
authors.forename: Angela
authors.initials: A
authors.lastname: Liloia
authors.forename: Marco
authors.initials: M
authors.lastname: Busnelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Giovannoni
authors.forename: Leo Edmond
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Lara
authors.initials: L
authors.lastname: Mainetti
authors.forename: Matteo
authors.initials: M
authors.lastname: Villa
authors.forename: Fritz Heintz
authors.initials: FH
authors.lastname: Bach
authors.forename: Biagio Eugenio
authors.initials: BE
authors.lastname: Leone
authors.forename: Giorgio Maria
authors.initials: GM
authors.lastname: Biasi
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Lavitrano
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000293:injuries* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D053148:Caspase 3