Boston - American Association for Thoracic Surgery

89 TH ANNUAL MEETING MAY 9–MAY 13, 2009BOSTON, MASSACHUSETTSF9. Reduced Oxidative Stress Response in the Ascending Aorta ofBicuspid Aortic Valve Patients: Impact on the ExtracellularMatrixJulie A. Phillippi, Michael A. Eskay, Bruce R. Pitt, Thomas G. GleasonDivision of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USAInvited Discussant: Frank W. SellkeOBJECTIVE: Our goal is to reveal the mechanisms that govern extracellularmatrix (ECM) degradation and smooth muscle cell (SMC) apoptosis in theascending aorta of bicuspid aortic valve (BAV) patients. We recently showed thatexpression and induction of metallothionein (MT) is reduced in BAV-associatedaneurysms relative to controls. MT is stimulated by oxidative stresses (OS) andheavy metal exposure and is known to regulate cell survival via vascular endothelialgrowth factor (Vegf) expression in other cell systems. We hypothesize thatreduced OS responses occur among BAV-aortic SMCs that cause dysregulation ofthe ECM leading to aneurysm formation. We sought to characterize the role of MTin the OS response of BAV-aortic SMCs and examine its impact on ECM regulation.METHODS: Ascending aorta was harvested during aortic surgery in BAV and tricuspidaortic valve (TAV) patients and from transplant donors. Aortic samples wereexclusively from males controlled for age and comorbidity. Tissue and aortic-SMCswere analyzed for ECM and cell survival gene expression at baseline and under OSin vitro. SMCs were cultured in the presence of CdCl 2 to induce MT expression.MT-null mice were used to help delineate the role of MT in ECM regulation in theaorta. Data were compared by ANOVA with Tukey-Kramer post hoc tests. Age waseliminated as a covariance by an analysis of regression.RESULTS: Under OS conditions, BAV-aortic SMCs exhibited significantly lessinducible Vegf than controls or TAV as did MT-null mice relative to wild-type, andaortic SMCs from MT-null mice had significantly lower cell viability. Treatment ofBAV-aortic SMCs with CdCl 2 prior to culture under OS conditions improved cellviability to a significantly less extent than for controls or TAV. BAV-aorta andmurine MT-null aorta exhibited significantly greater col I gene expression.CONCLUSION: Limited SMC protection from OS by cadmium further supportsa role for MT in regulating OS responses in BAV-aorta. These results are consistentwith our previous report that cadmium-induced MT was lower in BAV than incontrol SMCs. Increased col I is seen in BAV-aorta and MT-null aorta when MTand Vegf expression and induction is reduced, strongly suggesting that OS responsevia MT plays an important role in ECM homeostasis in the ascending aorta. Thesedata continue to support our hypothesis that BAV SMCs lack a sufficient OSresponse to maintain aortic ECM homeostasis which imparts a predisposition toascending aortic aneurysm formation.134