Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve

Björck, Hanna M.; Du, Lei; Pulignani, Silvia; Paloschi, Valentina; Lundströmer, Karin; Kostina, Aleksandra; Österholm, Cecilia; Malashicheva, Anna; Kostareva, Anna; Evangelista, Arturo; Teixidó-Turà, Gisela; Maleki, Shohreh; Franco‐Cereceda, Anders; Eriksson, Per

doi:10.1038/s41598-018-20642-4

Cited by 30 publications

(26 citation statements)

References 59 publications

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“…Thus, the immaturity in BAV can turn into premature senescence with all accompanying consequences. Our collective data on differentially regulated pathways between BAV and TAV i.e., hypoxia, oncogene-related pathways such as WNT or MYC, and UV response may well be due to premature senescence (16,110,111), giving support to the possibility of EndMT/EMT conversion to senescence and aortic degeneration in BAV. Compatible with shorter telomeres and senescence-induced activation of cell cycle checkpoint, we also observed significantly increased protein expression of the cyclindependent kinase inhibitor P27 (the product of CDKN1B gene) in non-dilated BAV AscA (16).…”

Section: Premature Aging and Bav Aortopathymentioning

confidence: 59%

“…(48). Lastly, DNA methylation studies further showed enrichment of EMT genes in non-dilated AscA of BAV patients (111). Similarly, analysis of intima-media in dilated AscA of BAV and TAV patients identified EMT as the top GO term and several key transcription factors for EMT, including ZEB1, SNAI2, and TWIST2, were hypomethylated in dilated BAV aorta.…”

Section: Non-physiological Shear Stress and Induction Of Endmt/emtmentioning

confidence: 83%

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Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

Maleki

Poujade

Bergman

et al. 2019

Front. Cardiovasc. Med.

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Thoracic aortic aneurysm (TAA) is the progressive enlargement of the aorta due to destructive changes in the connective tissue of the aortic wall. Aneurysm development is silent and often first manifested by the drastic events of aortic dissection or rupture. As yet, therapeutic agents that halt or reverse the process of aortic wall deterioration are absent, and the only available therapeutic recommendation is elective prophylactic surgical intervention. Being born with a bicuspid instead of the normal tricuspid aortic valve (TAV) is a major risk factor for developing aneurysm in the ascending aorta later in life. Although the pathophysiology of the increased aneurysm susceptibility is not known, recent studies are suggestive of a transformation of aortic endothelium into a more mesenchymal state i.e., an endothelial-to-mesenchymal transition in these individuals. This process involves the loss of endothelial cell features, resulting in junction instability and enhanced vascular permeability of the ascending aorta that may lay the ground for increased aneurysm susceptibility. This finding differentiates and further emphasizes the specific characteristics of aneurysm development in individuals with a bicuspid aortic valve (BAV). This review discusses the possibility of a developmental fate shared between the aortic endothelium and aortic valves. It further speculates about the impact of aortic endothelium phenotypic shift on aneurysm development in individuals with a BAV and revisits previous studies in the light of the new findings.

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Section: Premature Aging and Bav Aortopathymentioning

confidence: 59%

Section: Non-physiological Shear Stress and Induction Of Endmt/emtmentioning

confidence: 83%

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

Maleki

Poujade

Bergman

et al. 2019

Front. Cardiovasc. Med.

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“…We found that LPS-challenged cells underwent a significant increase in the global DNA methylation profile paralleled by a significant decrease in global hydroxymethylation ( Figure 7 a). Emerging evidence suggests that DNA methylation and hydroxymethylation variations are required for EMT [ 47 , 48 , 49 ], a multistep and progressive phenomenon, consisting of loss of the epithelial and acquisition of a mesenchymal phenotype, associated with cell transformation, playing a major role in a variety of diseases, including airway remodeling in asthma [ 26 , 50 ] and cancer [ 17 , 50 ]. Hence, we subsequently investigated whether the LPS-challenged cells exposed to AuNPs could undergo EMT and whether this transformation could be causatively linked to the observed MG-H1 accumulation.…”

Section: Resultsmentioning

confidence: 99%

“…Again, AG treatment prevented both epigenetic modifications, suggesting a causative role of MG-dependent glycative stress in triggering these processes in LPS-challenged AuNPs-exposed BEAS-2B and A549 cells. Emerging evidence suggests that global DNA methylation and hydroxymethylation variations are required for EMT [ 47 , 48 , 49 ]. Since we found that MG-H1 controlled both DNA global modifications and EMT, we speculate that this MG-derived AGE can be an additional agent linking these two phenomena.…”

Section: Discussionmentioning

confidence: 99%

Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity

et al. 2020

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Gold nanoparticles (AuNPs) are considered nontoxic upon acute exposure, at least when they are equal or above 5 nm size. However, the safeguard mechanisms contributing to maintain cell viability are scarcely explored so far. Here, we investigated the cyto-protective role of Glyoxalase 1 (Glo1), a key enzyme involved in the control of deleterious dicarbonyl stress, in two human cell types of the respiratory tract, after an acute exposure to AuNPs with a main size of 5 nm. We found that the redox sensitive Nrf-2-mediated up-regulation of Glo1 was crucial to protect cells from AuNPs-induced toxicity. However, cells challenged with a pro-inflammatory/pro-oxidative insult become susceptible to the pro-apoptotic effect of AuNPs. Notably, the surviving cells undergo epigenetic changes associated with the onset of a partial epithelial to mesenchymal transition (EMT) process (metastable phenotype), driven by the increase in dicarbonyl stress, consequent to Glo1 inactivation. As a physiological respiratory epithelium is required for the normal respiratory function, the knowledge of the protective mechanisms avoiding or (when challenged) promoting its modification/damage might provide insight into the genesis, and, most importantly, prevention of potential health effects that might occur in subjects exposed to AuNPs, through targeted surveillance programs, at least under specific influencing factors.

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“…Other mutated gene often correlated with specific features and prognosis. Due to abnormal flow in BAV aneurysm, the aberrant methylation of epithelial-mesenchymal-transition and increased expression of WNT/β-catenin genes like MYLK, ZEB1 were involved (Bjorck et al, 2018). Besides, transcriptome analyses and immunohistochemical study of ascending aortic specimens from BAV patients showed that receptor tyrosine kinase (RTK)/p-AKT pathway in the middle part of ascending aortic wall was activated, in spite of the constant expression level of total AKT (Hirata et al, 2018; Yamashita et al, 2018).…”

Section: Genetics: Polymorphism and Complexity Of The Pathogenesismentioning

confidence: 99%

Bicuspid Aortic Valve: An Update in Morphology, Genetics, Biomarker, Complications, Imaging Diagnosis and Treatment

Liu

Xie

et al. 2019

Front. Physiol.

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The bicuspid aortic valve, a kind of heart disease that comes from parents, has been paid attention around the world. Although most bicuspid aortic valve (BAV) patients will suffer from some complications including aortic stenosis, aortic regurgitation, endocarditis, and heart dysfunction in the late stage of the disease, there is none symptom in the childhood, which restrains us to diagnose and treatment in the onset phase of BAV. Hemodynamic abnormalities induced by the malformations of the valves in BAV patients for a long time will cause BAV-associated aortopathy: including progress aortic dilation, aneurysm, dissection and rupture, cardiac cyst and even sudden death. At present, preventive surgical intervention is the only effective method used in this situation and the diameter of the aorta is the primary reference criterion for surgery. And the treatment effects are always not satisfactory for patients and clinicians. Therefore, we need more methods to evaluate the progression of BAV and the surgery value and the appropriate intervention time by combining basic research with clinical treatment. In this review, advances in morphology, genetic, biomarkers, diagnosis and treatments are summarized, which expects to provide an update about BAV. It is our supreme expectations to provide some evidences for BAV early screening and diagnosis, and in our opinion, personalized surgical strategy is the trend of future BAV treatment.

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Altered DNA methylation indicates an oscillatory flow mediated epithelial-to-mesenchymal transition signature in ascending aorta of patients with bicuspid aortic valve

Cited by 30 publications

References 59 publications

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

Endothelial/Epithelial Mesenchymal Transition in Ascending Aortas of Patients With Bicuspid Aortic Valve

Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity

Bicuspid Aortic Valve: An Update in Morphology, Genetics, Biomarker, Complications, Imaging Diagnosis and Treatment

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