Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study

Folkersen, Lasse; Wågsäter, Dick; Paloschi, Valentina; Jackson, Veronica; Petrini, Johan; Kurtovic, Sanela; Maleki, Shohreh; Eriksson, Maria; Caidahl, Kenneth; Hamsten, Anders; Michel, Jean‐Baptiste; Líška, Ján; Gabrielsen, Anders; Franco‐Cereceda, Anders; Eriksson, Per

doi:10.2119/molmed.2011.00286

Cited by 85 publications

(103 citation statements)

References 25 publications

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“…32 Although peroxidase activity was found to be elevated in aortic specimens from patients with BAV, total SOD activity remained similar between patient cohorts in the present study. These results are in line with our recent study showing that the expression of the 3 SOD isoforms is either similar ( Sod1 ) or decreased ( Sod2 and Sod3 ) in the R region of the BAV ascending aorta, which corresponds to the aortic segment proximally adjacent to the right coronary sinus.…”

Section: Discussionsupporting

confidence: 38%

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Billaud

Phillippi

Kotlarczyk

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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Objective Congenital bicuspid aortic valve (BAV) is distinctly associated with the development of ascending aortopathy in adulthood, portending risk of both ascending aortic aneurysm and dissection. Our previous work implicated deficiency in oxidative stress response as a mediator of the BAV-associated aortopathy. We hypothesize that reactive oxygen species generation invokes elevated local oxidative tissue damage in ascending aorta of patients with BAV. Methods Ascending aortic specimens were obtained from patients undergoing elective aortic replacement and/or aortic valve replacement and during heart transplant operations. Levels of superoxide anion were measured via high-pressure liquid chromatography–based detection of 2-hydroxyethidium in aortic specimens. Lipid peroxidation and enzymatic activity of superoxide dismutase and peroxidase were quantified in aortic specimens. Results Superoxide anion production was elevated in aortic specimens from patients with nonaneurysmal BAV (n = 59) compared with specimens from patients with the morphologically normal tricuspid aortic valve (TAV, n = 38). Total superoxide dismutase activity was similar among aortic specimens from patients with TAV versus BAV (n = 27 and 26, respectively), whereas peroxidase activity was increased in aortic specimens from patients with BAV compared with specimens from patients with TAV (n = 14 for both groups). Lipid peroxidation was elevated in aortic specimens from BAV patients compared with TAV patients (n = 14 and 11, respectively). Conclusions Superoxide anion accumulation and increased lipid peroxidation demonstrate that, despite increased peroxidase activity, the ascending aortopathy of patients with BAV involves oxidative stress. In addition, the absence of increased superoxide dismutase activity in BAV specimens indicates a deficiency in antioxidant defense. This suggests that the characteristic smooth muscle cell loss observed in BAV aortopathy may be a consequence of superoxidemediated cell damage.

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Section: Discussionsupporting

confidence: 38%

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Billaud

Phillippi

Kotlarczyk

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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“…The resulting genes were then analyzed in expression profiles of vascular tissues in these patients. 14 Our findings suggest that there is no inherent difference between BAV and TAV with respect to TGFβ signaling; instead, the bioavailability and effects of active TGFβ are muted in patients with BAV.…”

Section: Arterioscler Thromb Vasc Biol April 2015mentioning

confidence: 60%

“…By principal component analysis analysis of these 217 genes using the ASAP expression database, 14 we noted a separation between BAV and TAV patients only in dilated aortas, suggesting increased activity of TGFβ during aneurysm development. Indeed, our in vitro cell system was valuable in identifying TGFβ-responsive genes, which can be used to study the molecular aspects of aneurysm formation in vivo.…”

Section: Discussionmentioning

confidence: 89%

Aneurysm Development in Patients With a Bicuspid Aortic Valve Is Not Associated With Transforming Growth Factor-β Activation

Paloschi

Gådin

Khan

et al. 2015

ATVB

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Objective-Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysms.Transforming growth factor-β (TGFβ) is a crucial factor of vascular remodeling, the impaired signaling of which can alter the structure and composition of the extracellular matrix. In this study, we analyzed the activity of TGFβ in aneurysmal and nonaneurysmal ascending aorta from BAV patients, using tricuspid aortic valve (TAV) patients as a reference group. Approach and Results-The response to exogenous TGFβ was analyzed with regard to gene expression in primary aortic smooth muscle cells that were isolated from 7 BAV and 5 TAV patients and in valve fibroblasts from 7 BAV and 8 TAV patients. The set of genes that were significantly changed by TGFβ (217 genes) was compared with gene expression profiles of the ascending aorta from BAV and TAV patients (139 arrays). By principle component analysis, based on the 217 genes, gene expression differed significantly in the intima/media region between aneurysmal BAV and TAV aortas, driven by the response in TAV patients. During aneurysm development the levels of phosphorylated SMADs and the availability of free TGFβ were lower in BAV patients compared with TAV. Confocal microscopy analysis showed a higher colocalization of latency associated peptide and latent TGFβ binding protein 3 in BAV aortas. as a biologically inactive form in the extracellular matrix in the large latent TGFβ1 complex, which contains a TGFβ1 homodimer, latency-associated peptide (LAP), and latent TGFβ1-binding proteins (LTBPs). Alternatively, TGFβ1 is bound in the small latent complex, which comprises a TGFβ1 homodimer and LAP. Release of the large latent complex from the extracellular matrix (catalyzed by metalloproteinases) and dissociation of TGFβ1 from LAP are required for its activation and biological activity. The pathophysiological mechanisms of BAV-associated aortopathy are unknown, but TGFβ signaling has been implicated in BAV pathology. 8,9 Previous studies have suggested that the development of aneurysm in BAV patients is characterized by lower TGFβ activity compared with tricuspid aortic valve (TAV) patients, distinguishing BAV-associated aneurysms from monogenic TAAs, based on data that fibrosis, which is stimulated by TGFβ, 10 increases during the development of aneurysms in TAV but not BAV patients. Conclusions-Our11,12 Moreover, inclusion of the extra domain A exon in the fibronectin gene, which is upregulated by TGFβ, is more frequent during the development of aneurysms in TAV versus BAV patients. 13Because the lack of fibrosis and the differential splicing of fibronectin could be attributed to disparate TGFβ responses between BAV and TAV patients, we examined TGFβ signaling in aortic smooth muscle cells (AoSMCs) from BAV and TAV patients. To identify such differences in TGFβ responsiveness, gene expression profiles were constructed after TGFβ treatment of AoSMCs and valvular fibroblasts from patients with BAV and TAV. The resulting genes were then analyzed in express...

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“…LTBP4 also interacts with several other matrix molecules, including fibronectin. Kurtovic et al [5] demonstrated a defect in fibronectin expression and distribution in aortic aneurysm, specially related to BAV, and Folkersen et al [4], performing a complete gene expression profiling of BAV and TAV patients with or without dilation of the thoracic aorta, revealed that LTBP3 and LTBP4 were highly specific for dilation in BAV patients.…”

Section: Discussionmentioning

confidence: 99%

“…with tricuspid aortic valve (TAV) with respect to patients with BAV [3][4][5]. Since the presentation of ATAAs is normally a silent condition and a significant number of dissections occur outside of the parameters suggested by the guidelines, a biomarker that could detect and monitor the progress of an aneurysm would be extremely useful, especially for BAV patients in whom complications occur a decade earlier in life than in TAV patients.…”

mentioning

confidence: 99%

Hypothesis-free secretome analysis of thoracic aortic aneurysm reinforces the central role of TGF-β cascade in patients with bicuspid aortic valve

Rocchiccioli

Cecchettini

Panesi

et al. 2017

Journal of Cardiology

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Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study

Cited by 85 publications

References 25 publications

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Aneurysm Development in Patients With a Bicuspid Aortic Valve Is Not Associated With Transforming Growth Factor-β Activation

Hypothesis-free secretome analysis of thoracic aortic aneurysm reinforces the central role of TGF-β cascade in patients with bicuspid aortic valve

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