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Reduced oxidative stress response in the ascending aorta of bicuspid aortic valve patients: impact on the extracellular matrix
Julie A. Phillippi, Michael A. Eskay, Bruce R. Pitt, Thomas G. Gleason; Division of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA
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Objective: Our goal is to reveal the mechanisms that govern extracellular matrix (ECM) degradation and smooth muscle cell (SMC) apoptosis in the ascending aorta of bicuspid aortic valve (BAV) patients. We recently showed that expression and induction of metallothionein (MT) is reduced in BAV-associated aneurysms relative to controls. MT is stimulated by oxidative stresses (OS) and heavy metal exposure and is known to regulate cell survival via vascular endothelial growth factor (Vegf) expression in other cell systems. We hypothesize that reduced OS responses occur among BAV-aortic SMCs that cause dysregulation of the ECM leading to aneurysm formation. We sought to characterize the role of MT in 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 tricuspid aortic valve (TAV) patients and from transplant donors. Aortic samples were exclusively from males controlled for age and comorbidity. Tissue and aortic-SMCs were analyzed for ECM and cell survival gene expression at baseline and under OS in vitro. SMCs were cultured in the presence of CdCl2 to induce MT expression. MT-null mice were used to help delineate the role of MT in ECM regulation in the aorta. Data were compared by ANOVA with Tukey-Kramer post hoc tests. Age was eliminated as a covariance by an analysis of regression.
Results: Under OS conditions, BAV-aortic SMCs exhibited significantly less inducible Vegf than controls or TAV as did MT-null mice relative to wild-type, and aortic SMCs from MT-null mice had significantly lower cell viability. Treatment of BAV-aortic SMCs with CdCl2 prior to culture under OS conditions improved cell viability to a significantly less extent than for controls or TAV. BAV-aorta and murine MT-null aorta exhibited significantly greater col I gene expression.
Conclusion: Limited SMC protection from OS by cadmium further supports a role for MT in regulating OS responses in BAV-aorta. These results are consistent with our previous report that cadmium-induced MT was lower in BAV than in control SMCs. Increased col I is seen in BAV-aorta and MT-null aorta when MT and Vegf expression and induction is reduced, strongly suggesting that OS response via MT plays an important role in ECM homeostasis in the ascending aorta. These data continue to support our hypothesis that BAV SMCs lack a sufficient OS response to maintain aortic ECM homeostasis which imparts a predisposition to ascending aortic aneurysm formation.
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