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Bossé, Yohan

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Bossé
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Yohan
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Université Laval. Département de médecine moléculaire
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Voici les éléments 1 - 10 sur 60
  • Publication
    Restreint
    Altered DNA methylation of long noncoding RNA H19 in calcific aortic valve disease promotes mineralization by silencing NOTCH1
    (American Heart Association, 2016-12-06) Gaudreault, Nathalie; Bouchareb, Rihab; Guay, Simon-Pierre; Amellah, Soumiya; Mkannez, Guada; Tremblay-Marchand, Joël; Boulanger, Marie-Chloé; Guauque-Olarte, Sandra; Bossé, Yohan; Pibarot, Philippe; Hadji, Fayez; Bouchard, Luigi; Nsaibia, Mohamed Jalloul; Mathieu, Patrick
    Background: Calcific aortic valve disease is characterized by an abnormal mineralization of the aortic valve. Osteogenic activity in the aortic valve is under the control of NOTCH1, which regulates the expression of key pro-osteogenic genes such as RUNX2 and BMP2. Long noncoding RNAs (lncRNAs) may reprogram cells by altering the gene expression pattern. Methods: Multidimensional genomic profiling was performed in human aortic valves to document the expression of lncRNAs and the DNA methylation pattern in calcific aortic valve disease. In-depth functional assays were carried out to document the impact of lncRNA on the mineralization of the aortic valve. Results: We documented that lncRNA H19 (H19) was increased in calcific aortic valve disease. Hypomethylation of the promoter region was observed in mineralized aortic valves and was inversely associated with H19 expression. Knockdown and overexpression experiments showed that H19 induces a strong osteogenic phenotype by altering the NOTCH1 pathway. Gene promoter analyses showed that H19 silenced NOTCH1 by preventing the recruitment of p53 to its promoter. A knockdown of H19 in valve interstitial cells (VICs) increased the expression of NOTCH1 and decreased the level of RUNX2 and BMP2, 2 downstream targets repressed by NOTCH1. In rescue experiments, the transfection of a vector encoding for the active Notch intracellular domain prevented H19-induced mineralization of valve interstitial cells. Conclusions: These findings indicate that a dysregulation of DNA methylation in the promoter of H19 during calcific aortic valve disease is associated with a higher expression of this lncRNA, which promotes an osteogenic program by interfering with the expression of NOTCH1.
  • Publication
    Restreint
    Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves
    (Lippincott Williams & Wilkins, 2009-10-01) Miqdad, Ahmed; Fournier, Dominique; Bossé, Yohan; Pépin, Andrée; Pibarot, Philippe; Mathieu, Patrick
    Background— Calcific aortic valve stenosis (AS) is a major societal and economic burden that is rising after the current shift toward an older population. Understanding the pathobiology of AS is crucial to implementing better preventive and therapeutic options. Research conducted during the past decade clearly points to active molecular and cellular processes involved in disease pathogenesis. However, no genomic approaches were used to identify genes and pathways that are differentially regulated in aortic valves of patients with and without AS. Methods and Results— A large-scale quantitative measurements of gene expression was performed on 5 normal and 5 AS valves using Affymetrix GeneChips. A total of 409 and 306 genes were significantly up- and downregulated in AS valves, respectively. The 2 most highly upregulated genes were matrix metalloproteinase 12 and chitinase 3-like 1. The upregulation of these 2 biologically relevant genes in AS was validated by real-time polymerase chain reaction in 38 aortic valves (12 normal and 26 AS). To provide a global biological validation of the whole-genome gene expression analysis, the microarray experiment was repeated in a second set of aortic valves with (n=5) or without (n=5) AS. There was an overrepresentation of small P values among genes claimed significant in the first microarray experiment. A total of 223 genes were replicated (P<0.05 and fold change >1.2), including matrix metalloproteinase 12 and chitinase 3-like 1. Conclusions— This study reveals many unrecognized genes potentially implicated in the pathogenesis of AS. These new genes were overlaid on known pathological pathways leading to AS to refine our molecular understanding of this disease.
  • Publication
    Accès libre
    The pathology and pathobiology of bicuspid aortic valve : State of the art and novel research perspectives
    (Wiley Blackwell, 2015-06-24) Bédard, Élisabeth; Nieto-Dorantes, Arturo; Huggins, Gordon; Boulanger, Marie-Chloé; Della Corte, Alessandro; Bossé, Yohan; Pibarot, Philippe; Michelena, Hector I.; Mathieu, Patrick; Limongelli, Giuseppe; Citro, Rodolfo; Body, Simon C.; Nemer, Mona; Schoen, Frederick J.
    Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long-term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved
  • Publication
    Restreint
    RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing
    (American Physiological Society, 2016-10-01) Gaudreault, Nathalie; Tremblay-Marchand, Joël; Kalavrouziotis, Dimitri; Droit, Arnaud; Guauque-Olarte, Sandra; Bossé, Yohan; Seidman, Jonathan G.; Pibarot, Philippe; Body, Simon C.; Dagenais, François.; Mathieu, Patrick
    The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves.
  • Publication
    Restreint
    Association between plasma lipoprotein levels and bioprosthetic valve structural degeneration
    (BMJ, 2016-07-04) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Larose, Éric; Mahjoub, Haïfa; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Després, Jean-Pierre; Nsaibia, Mohamed Jalloul; Mathieu, Patrick
    Introduction: Structural valve degeneration (SVD) leads to the failure of aortic valve bioprostheses. It is suspected that lipid-derived factors could play a role in SVD. We hypothesised that oxidised low-density lipoprotein (OxLDL), OxLDL/LDL, OxLDL/high-density lipoprotein (OxLDL/HDL) and proprotein convertase subtilisin/kexin 9 (PCSK9) may be associated with SVD. Methods: We included 199 patients who underwent an aortic valve replacement with a bioprosthesis and had an echocardiography follow-up to evaluate the function of the prosthesis. SVD was defined as an increase in mean transprosthetic gradient (=10 mm Hg) or a worsening of transprosthetic regurgitation (=1/3) during the follow-up. Results: After a mean follow-up of 8±3.5 years, 41(21%) patients developed SVD. The univariate predictors of SVD were LDL (p=0.03), apolipoprotein B (p=0.01), OxLDL (p=0.02), OxLDL/HDL (p=0.009) and LDL associated with small, dense particles (LDL-C<255Å) (p=0.02). In a model adjusted for covariates, only OxLDL/HDL (OR 1.49, 95%CI 1.08 to 2.07 per 10 units, p=0.01) remained associated with SVD. There was a significant interaction between OxLDL/HDL and PCSK9 on SVD (p=0.05). After adjustment, compared with patients with low OxLDL/HDL (median, <25.4) and low PCSK9 (median, <298 ng/mL) (referent), patients with both an elevated OxLDL/HDL ratio and PCSK9 had a higher risk of SVD (OR 2.93, 95% CI 1.02 to 9.29, p=0.04). Conclusions: OxLDL/HDL ratio is independently associated with SVD.
  • Publication
    Accès libre
    Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis : is valvular fibrosis the explanation?
    (Grune & Stratton, 2016-11-22) Trahan, Sylvain; Couture, Christian; Mohammadi, Siamak; Côté, Nancy; Joubert, Philippe; Bossé, Yohan; Clavel, Marie-Annick; Pagé, Sylvain; Dagenais, François.; Mathieu, Patrick; Simard, Louis
    Rationale: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification (AVC) loads than men for the same AS hemodynamic severity. Objective: We thus aimed to assess sex-differences in aortic valve fibro-calcific remodelling. Methods and Results: One hundred and twenty-five patients underwent Doppler-echocardiography and multidetector-computed-tomography within 3 months prior to aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed and fibrosis degree was determined. Sixty-four men and 39 women were frequency-matched for age, body mass index (BMI), hypertension, renal disease, diabetes, and AS severity. Mean age was 75±9years, mean gradient (41±18mmHg) and indexed aortic valve area (0.41±0.12cm2/m2) were similar between men and women (all p=0.18). Median AVC (1973[1124-3490]AU) and mean valve weight (2.36±0.99g) were lower in women compared to men (both p<0.0001). AVC density correlated better with valve weight in men (r2=0.57; p<0.0001) than in women (r2=0.26; p=0.0008). After adjustment for age, BMI, AVC density and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (p=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (p=0.01) and Masson's trichrome staining revealed a greater proportion of dense connective tissue (p=0.02) in women compared to men. Conclusions: In this series with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared to men. These findings suggest that the pathophysiology of the disease and thus potential targets for drug development may be different according to sex.
  • Publication
    Accès libre
    High expression of the Pi-transporter SLC20A1/Pit1 in calcific aortic valve disease promotes mineralization through regulation of Akt-1
    (Public Library of Science, 2013-01-04) Fournier, Dominique; Boulanger, Marie-Chloé; Bossé, Yohan; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Mathieu, Patrick
    The regulation of phosphate (Pi) handling is crucial during calcification of the aortic valve. Gene profiling of Pi transporters revealed that VIC culture expresses SLC201A1/Pit1 and SLC20A2/Pit2. On exposure to a mineralizing medium (2 mM Pi), the expression of Pi transporters in VIC culture is increased several folds, with the highest magnitude for SLC20A1. By using siRNAs, we established that silencing SLC20A1 significantly reduced Pi-induced mineralization of VICs. In human pathological specimens, we found that the expression of SCL20A1 was increased in CAVD tissues compared to control non-mineralized aortic valves. Treatment of VIC culture with Pi promoted the loss of mitochondrial membrane potential (ΔΨm) and cytochrome c release within the cytosol, leading to apoptosis. Inhibition of Pi transporters with phosphonoformic acid (PFA) prevented Pi-mediated apoptosis of VICs. Moreover, we discovered that the level of the Akt-1 transcript is diminished in CAVD tissues compared with control valves. Accordingly, treatment with Pi caused a reduction of the Akt-1 transcript in VIC culture, and treatment with PFA or siRNA against SLC20A1 restored the level of Akt-1. Overexpression of Akt-1 (pCMVAkt-1) prevented both Pi-induced apoptosis and mineralization of VIC culture. These results strongly suggest that overexpression of SLC20A1 promotes apoptosis and mineralization by altering the level of Akt-1.
  • Publication
    Restreint
    Inflammation is associated with the remodeling of calcific aortic valve disease
    (Kluwer Academic Publishers, 2012-12-09) Trahan, Sylvain; Fournier, Dominique; Couture, Christian; Côté, Nancy; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Pagé, Sylvain; Mathieu, Patrick
    Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder. Studies indicate that mineralization of the aortic valve may be related to the inflammatory process. However, no clear evidence has been given regarding clinical evolution of aortic stenosis and the inflammatory process within the aortic valve. Aortic valves excised from 285 patients with CAVD undergoing aortic valve replacement were analyzed for the presence of chronic inflammatory infiltrates, and those findings were related to the hemodynamic severity of aortic stenosis. In a subset of 57 patients, in whom additional valvular tissue and the clinical progression rate of aortic stenosis were available, the density of leukocytes was determined as well as the number of TNF-a transcripts. Histological analyses revealed that in 81 (28.4 %) patients, the presence of chronic inflammatory infiltrates was documented within CAVD tissue, which was characterized by the existence of a cluster of cells as well as the presence of neovascularisation and osseous metaplasia. The presence of an inflammatory process within the CAVD tissue was independently related to the remodeling process and the peak transaortic gradient. In addition, the density of leukocytes within CAVD tended to correlate (r¿=¿0.25, p¿=¿0.05) with the progression rate of aortic stenosis. Dense inflammatory infiltrate within CAVD is associated with an active remodeling process, the severity of aortic stenosis, and the hemodynamic progression rate.
  • Publication
    Restreint
    Amyloid substance within stenotic aortic valves promotes mineralization
    (Blackwell Scientific, 2012-10-01) Audet, Audrey; Couture, Christian; Côté, Nancy; Bossé, Yohan; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick
    AIMS: Accumulation of apolipoproteins may play an important role in the pathobiology of calcific aortic valve disease (CAVD). We aimed to explore the hypothesis that apolipoprotein-derived amyloid could play a role in the development of CAVD. METHODS AND RESULTS: In 70 explanted CAVD valves and 15 control non-calcified aortic valves, we assessed the presence of amyloid by using Congo red staining. Immunohistochemistry was performed to document the presence of apolipoprotein AI (Apo-AI). Apoptosis was documented by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) studies performed in control and CAVD valves. Control valves were free of amyloid. Deposition of amyloid was detected in all CAVD valves, and the amount was positively correlated with plasma high-density lipoprotein and Apo-AI levels. Apo-AI within CAVD valves co-localized with intense staining of fibrillar amyloid. In turn, deposition of amyloid co-localized with apoptosis near mineralized areas. Isolation of amyloid fibrils confirmed that Apo-AI is a major component of amyloid deposits in CAVD. In vitro, CAVD-derived amyloid extracts increased apoptosis and mineralization of isolated aortic valvular interstitial cells. CONCLUSION: Apo-AI is a major component of amyloid substance present within CAVD valves. Furthermore, amyloid deposits participate in mineralization in CAVD by promoting apoptosis of valvular interstitial cells.
  • Publication
    Restreint
    Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease : implications for valve mineralization.
    (Elsevier Biomedical, 2014-02-11) Bouchareb, Rihab; Fournier, Dominique; Boulanger, Marie-Chloé; Bossé, Yohan; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick
    OBJECTIVES: This study sought to document the presence and role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in calcific aortic valve disease (CAVD). BACKGROUND: CAVD is a chronic disorder characterized by pathological mineralization and remodeling. Studies have indicated that human CAVD tissues are infiltrated by lipids and that inflammation may play a role in the pathobiology. We hypothesized that Lp-PLA2 (encoded by the PLA2G7 gene) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells. METHODS: We have documented the expression of the phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. Messenger ribonucleic acid and protein expression were confirmed in aortic valves explanted from 60 patients by quantitative polymerase chain reaction and immunohistochemistry, respectively. The effect of lysophosphatidylcholine, the product of Lp-PLA2 activity, was documented on the mineralization of valve interstitial cell cultures. RESULTS: Transcriptomic analyses of CAVD and control nonmineralized aortic valves revealed that Lp-PLA2 was increased by 4.2-fold in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by quantitative polymerase chain reaction, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indexes of tissue remodeling. In vitro, lysophosphatidylcholine increased the expression of alkaline phosphatase, the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme, sodium-dependent phosphate cotransporter 1 (encoded by the SLC20A1 gene), and osteopontin. We then showed that lysophosphatidylcholine-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a protein-kinase-A-dependent pathway. CONCLUSIONS: Together, these results demonstrated that Lp-PLA2 is highly expressed in CAVD, and it plays a role in the mineralization of valve interstitial cells. Further work is necessary to document whether Lp-PLA2 could be considered as a novel target in CAVD.