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Bouchareb, Rihab

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Rihab

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Voici les éléments 1 - 7 sur 7
  • PublicationAccès libre
    Soluble CD14 is associated with the structural failure of bioprostheses
    (Elsevier, 2018-06-30) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Mkannez, Ghada; Boulanger, Marie-Chloé; Bossé, Yohan; Pibarot, Philippe; Clavel, Marie-Annick; Nsaibia, Mohamed Jalloul; Mathieu, Patrick; Salaun, Erwan
    Introduction: Aortic valve bioprostheses, which do not mandate chronic anticoagulation, are prone to structural valve degeneration (SVD). The processes involved in SVD are likely multifactorial. We hypothesized that inflammation and macrophage activation could be involved in SVD. Methods: In 203 patients with an aortic valve bioprosthesis, we evaluated the association between the macrophage activation marker soluble CD14 (sCD14) and SVD. Results: After a mean follow-up of 8 ± 3 years, 42 (21%) patients developed SVD. Patients with SVD had higher peak (44 ± 13 mmHg vs. 25 ± 12 mmHg, p < .0001) and mean (24 ± 7 mmHg vs. 12 ± 5 mmHg, p < .0001) transprosthetic gradients. On univariable analysis, low-density lipoprotein cholesterol (LDL) and sCD14 were associated with SVD. After correction for covariates, sCD14 (OR: 1.12, 95%CI: 1.02–1.23, p = .01) remained independently associated with SVD. In turn, sCD14 was associated with the HOMA index and high-density lipoprotein (HDL) level. Patients with a metabolic syndrome (MetS) had higher level of sCD14. In a model corrected for age, sex, HOMA and HDL, the MetS remained independently associated with sCD14 levels (β = 0.65, SE = 0.30, p = .03). Conclusion: Circulating level of sCD14 is an independent predictor of SVD. In turn, patients with MetS have higher sCD14 levels.
  • PublicationRestreint
    Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease
    (Blackwell Scientific Publication, 2020-05-30) Simard, Sébastien; Bouchareb, Rihab; Arsenault, Benoit; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Witztum, Joseph L.; Pibarot, Philippe; Clavel, Marie-Annick; Nsaibia, Mohamed Jalloul; Mathieu, Patrick; Tsimikas, Sotirios
    Background Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX). Objective To determine the predictive value of circulating ATX mass and activity for CAVS. Methods We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples. Results Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL-apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03–1.10 per 10 ng mL−1, P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14–2.17 per 10 RFU min−1, P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL−1) or OxPL-apoB (<2.02 nmol L−1, median) levels (referent), patients with both higher ATX activity (≥84 RFU min−1) and Lp(a) (≥50 mg dL−1) (OR 3.46, 95% CI 1.40–8.58, P = 0.007) or OxPL-apoB (≥2.02 nmol L−1, median) (OR 5.48, 95% CI 2.45–12.27, P < 0.0001) had an elevated risk of CAVS. Conclusion Autotaxin is a novel and independent predictor of CAVS in patients with CAD.
  • PublicationRestreint
    Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve
    (American Heart Association, etc., 2015-08-25) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Trahan, Sylvain; Marette, André; Couture, Christian; Lépine, Jamie-Lee; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Hadji, Fayez; Pagé, Sylvain; Scipione, Corey A.; Nsaibia, Mohamed Jalloul; Romagnuolo, Rocco; Laflamme, Marie-Hélène; Koschinsky, Marlys L.; Mathieu, Patrick
    Background—Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids (OxPLs) with a high content in lysophosphatidylcholine (LPC). Autotaxin (ATX) transforms LPC into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve. Methods and Results—We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches we have also investigated the role of ATX- lysophosphatidic acid on the mineralization of isolated valves interstitial cells (VICs) and in a mouse model of CAVD. Enzyme specific ATX activity was elevated by 60% in mineralized aortic valves compared to control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which co-localized with OxPL and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that VICs also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promote the mineralization of the aortic valve through a NF-¿B/IL-6/BMP2 pathway. In LDLR-/-/ApoB100/100/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. Conclusions—ATX is transported in the aortic valve by Lp(a) and is also secreted by VICs. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent novel therapeutic targets in CAVD.
  • PublicationRestreint
    P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt : implication for calcific aortic valve disease
    (Academic Press Inc, Ltd., 2014-03-11) Bouchareb, Rihab; Fournier, Dominique; Boulanger, Marie-Chloé; Bossé, Yohan; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Laflamme, Marie-Hélène; Mathieu, Patrick
    Calcific aortic valve disease (CAVD) is a disorder characterized by an abnormal mineralization, which may have intricate links with inflammation. Interleukin-6 (IL-6) and its cognate cytokines are widely expressed and exert pleiotropic effects on different tissues. In this study, we examined the expression of the IL-6 family of cytokines in human CAVD by using a transcriptomic approach and we performed in-depth functional assays with valve interstitial cells (VICs) to unravel the process regulating IL-6 expression and its role during the mineralization of the aortic valve. We documented by both microarray and q-PCR analyses an elevated expression of IL-6 in human CAVD, which was correlated with the remodeling process. IL-6 was highly expressed by VICs. We found that following treatment with a phosphate-containing medium the level of IL-6 expressed by VICs increased by several-fold. Phosphate-induced expression of IL-6 relied on reduced PI3K/Akt signaling downstream of the P2Y2 receptor (P2Y2R). In this regard, we found by using transfection experiments that Akt-1 is a negative regulator of the NF-¿B pathway. In addition, by using a siRNA targeting IL-6 we found that phosphate-induced mineralization was largely dependent on IL-6 expression. A transfection of Akt-1 rescued the hypermineralizing phenotype of P2Y2R-/- mouse VICS (MVICs). Hence, we documented a novel mechanism whereby P2Y2R and Akt modulate the NF-¿B pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs
  • PublicationRestreint
    Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis.
    (Academic Press Inc, Ltd., 2016-03-11) Lachance, Dominic.; Bouchareb, Rihab; Asselin, Jérémie; Boudreau, Denis; Marette, André; Boulanger, Marie-Chloé; Le Quang, Khai; Côté, Nancy.; Bossé, Yohan; Shayhidin, Elnur Elyar; Messaddeq, Younès; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Hadji, Fayez; Mathieu, Patrick
    Aims: Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. Methods and results: By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R-/- mice. Measurements of extracellular pH (pHe) by using core–shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR-/-/ApoB100/100/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8 months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2 months. The administration of 2-thioUTP (2 mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR-/-/ApoB100/100/IGF2 mice. Conclusion: P2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.
  • PublicationRestreint
    Early development of calcific aortic valve disease and left ventricular hypertrophy in a mouse model of combined dyslipidemia and type 2 diabetes mellitus.
    (American Heart Association, 2014-08-14) Lachance, Dominic.; Bouchareb, Rihab; Kohen Avramoglu, Rita; Fournier, Dominique; Marette, André; Boulanger, Marie-Chloé; Le Quang, Khai; El Husseini, Diala; Fang, Xiang Ping; Pibarot, Philippe; Deshaies, Yves; Sweeney, Gary; Mathieu, Patrick; Laplante, Marc André
    Objective—This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus. Approach and Results—When compared with nondiabetic LDLr-/-/ApoB100/100, diabetic LDLr-/-/ApoB100/100/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr-/-/ApoB100/100/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr-/-/ ApoB100/100 mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr-/-/ApoB100/100/IGF-II mice when compared with LDLr-/-/ApoB100/100. Importantly, we found that peak aortic jet velocity was significantly increased in LDLr-/-/ApoB100/100/ IGF-II mice versus LDLr-/-/ApoB100/100 animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (anp, bnp, b-mhc) in myocardial tissues and of osteogenic genes (spp1, bglap, runx2) in aortic tissues of diabetic mice. Conclusions—We have established the diabetes mellitus –prone LDLr-/-/ApoB100/100/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
  • PublicationRestreint
    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.