Basal and Oxidative Stress–Induced Expression of Metallothionein Is Decreased in Ascending Aortic Aneurysms of Bicuspid Aortic Valve Patients

Abstract

Background Bicuspid aortic valve (BAV) is a heritable condition that has been linked by an unknown mechanism to a predisposition for ascending aortic aneurysm. Matrix metalloproteinases have been implicated in this predisposition. Metallothionein is a poorly characterized, metal-binding protein that regulates matrix metalloproteinases and is an antioxidant known to be upregulated under oxidative stress. Methods and Results To determine putative factors involved in the pathogenesis of aortic aneurysm in BAV patients, our first goal was to identify genes that are dysregulated in ascending aortic aneurysms of BAV patients compared with tricuspid aortic valve patients and nondiseased (control) donors. By microarray analysis (22 000 probe sets), 110 dysregulated genes were identified in BAV compared with tricuspid aortic valve patients and control donors; 8 were genes of the metallothionein family. Metallothionein gene expression and protein expression were significantly lower in aortic tissue and cultured aortic smooth muscle cells from BAV patients compared with control subjects. Matrix metalloproteinase-9 expression was increased in BAV aortic samples relative to controls. BAV aorta was more susceptible to oxidative stress, and induction of metallothionein under oxidative stress was reduced in BAV patients compared with control subjects. Conclusions These results demonstrate dysregulated metallothionein expression in ascending aortic smooth muscle cells of BAV patients that may contribute to an inadequate response to oxidative stress and provoke aneurysm formation. We hypothesize that metallothionein plays a pivotal role in the response of ascending aortic smooth muscle cells to oxidative stress cues normally involved in the maintenance of the extracellular matrix, including the regulation of matrix metalloproteinase expression.

Pathogenetic mechanisms of ascending aortic aneurysm of varied aetiology

“…Имеются данные, говорящие об уменьшении экспрессии гена металлотионина в тканях аорты пациентов с врожденным пороком сердца [8]. Пред-полагают, что дефицит металлотионина может при-водить к нарушению метаболизма внеклеточного матрикса и способствовать дегенерации сосудистой стенки в условиях гемодинамической нагрузки.…”

“…2). Нами не установлено связи между активностю ММП-2, -9 и возрастом обсле-дованных пациентов, что соответствует ранее опу-бликованным данным [8].…”

A preliminary proteomic evaluation of smooth muscle cells in thoracic aortic aneurysms

“…Indeed, during TAA development, the loss of SMCs through apoptosis results in major changes due to their physical absence in the dilated wall as well as differentially regulated gene and protein profiles, i.e. increased MMP expression (Koullias et al, 2004;Schmoker et al, 2007;Phillippi et al, 2009), further contributing to disease development.…”

Proteomic evidence for the plasticity of cultured vascular smooth muscle cells

“…There have been several reports studying vascular SMCs that were grown in different types of media ranging from regular media such as M199 (14,15), DMEM (16)(17)(18), or DMEM/F12 (19) supplemented with FBS, with or without the addition of the above mentioned growth factors, or commercially available media specially optimized for the growth of SMCs (20)(21)(22)(23). While the optimized media appear valuable in terms of being successful in establishing new primary cell lines and being able to passage longer, they are not cost-effective.…”