Papers by Dominique Fournier
Pathobiology, Aug 21, 2013
fibrosis score of the aortic valve even after correction for covariates. In addition, patients un... more fibrosis score of the aortic valve even after correction for covariates. In addition, patients under ARBs had lower aortic valve inflammation and expression of IL-6. Conclusions: These findings suggest that ARBs may alter the fibrotic process of the aortic valve in CAVD, possibly by lowering tissue inflammation.
Circulation, Nov 22, 2011
Journal of the American College of Cardiology
To document the presence and role of Lp-PLA2 in calcific aortic valve disease. Calcific aortic va... more To document the presence and role of Lp-PLA2 in calcific aortic valve disease. Calcific aortic valve disease (CAVD) is a chronic disorder characterized by pathological mineralization and remodelling. Studies have highlighted that human CAVD tissues are infiltrated by lipids and that inflammation may play a role into the pathobiology. We hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2/PLA2G7) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells (VICs). We have documented the expression of phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. mRNA and protein expression were confirmed in aortic valves explanted from 60 patients by q-PCR and immunohistochemistry, respectively. The effect of lysophosphatidylcholine (LPC), the product of Lp-PLA2 activity, was documented on the mineralization of VIC cultures. Transcriptomic analyses of CAVD and control non-mineralized aortic valves revealed that Lp-PLA2 ...
Health, 2010
Background: Although cardiac-related mortality rates are declining for the general population in ... more Background: Although cardiac-related mortality rates are declining for the general population in the United States, this is not the case for patients with diabetes. Diabetes is a significant independent predictor of atrial fibrillation (AF), the most common cardiac rhythm disturbance responsible for substantial morbidity and mortality. Objectives: This research was designed to evaluate properties of the atrial tissue between patients with and without type 2 diabetes. Heart rate variability (HRV) indices were calculated and expression of Kv1.5, connexin 43 (Cx43), and 40 (Cx40) were compared. Methods: Patients undergoing a CABG were enrolled: 10 with type 2 diabetes and 8 without diabetes, paired for age, gender and co-morbidities such as hypertension and dyslipidemia. All patients showed normal ejection fraction. A sample of right auricular appendix was taken during CABG and Kv1.5, Cx40 and Cx43 protein contents were determined by western blotting and normalized to α-tubulin level. Results: No HRV difference was found between patients with and without diabetes. Cx43 and Kv1.5 levels were unaffected by diabetes (p=0.20 and 0.07, respectively) whereas Cx40 content was significantly increased by 55% (p=0.02). Levels of Cx43 phosphorylated and non-phosphorylated forms were non-significantly decreased in patients with diabetes. Conclusion: Patients with type 2 diabetes had higher expression of Cx40 in the right auricular appendix tissue. In light of other studies having demonstrated a link between AF and Cx40 expression, it is possible that higher prevalence of AF in patients with diabetes is explained, at least partially, by differential expression of gap-junction proteins.
Journal of Molecular and Cellular Cardiology, 2014
Calcific aortic valve disease (CAVD) is a disorder characterized by an abnormal mineralization, w... more 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-κB 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-κB pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs.
Journal of Molecular and Cellular Cardiology, 2014
Calcific aortic valve disease (CAVD) is a chronic disorder characterized by an abnormal mineraliz... more Calcific aortic valve disease (CAVD) is a chronic disorder characterized by an abnormal mineralization of the leaflets, which is accelerated in bicuspid aortic valve (BAV). It is suspected that mechanical strain may promote/enhance mineralization of the aortic valve. However, the effect of mechanical strain and the involved pathways during mineralization of the aortic valve remains largely unknown. Valve interstitial cells (VICs) were isolated and studied under strain conditions. Human bicuspid aortic valves were examined as a model relevant to increase mechanical strain. Cyclic strain increased mineralization of VICs by several-fold. Scanning electron microscope (SEM) and energy dispersive X-ray (EDX) analyses revealed that mechanical strain promoted the formation of mineralized spheroid microparticles, which coalesced into larger structure at the surface of apoptotic VICs. Apoptosis and mineralization were closely associated with expression of ENPP1. Inhibition of ENPP1 greatly reduced mineralization of VIC cultures. Through several lines of evidence we showed that mechanical strain promoted the export of ENPP1-containing vesicles to the plasma membrane through a RhoA/ROCK pathway. Studies conducted in human BAV revealed the presence of spheroid mineralized structures along with the expression of ENPP1 in areas of high mechanical strain. Mechanical strain promotes the production and accumulation of spheroid mineralized microparticles by VICs, which may represent one important underlying mechanism involved in aortic valve mineralization. RhoA/ROCK-mediated export of ENPP1 to the plasma membrane promotes strain-induced mineralization of VICs.
Canadian Journal of Cardiology, 2013
Canadian Journal of Cardiology, 2013
To document the presence and role of Lp-PLA2 in calcific aortic valve disease. Background: Aortic... more To document the presence and role of Lp-PLA2 in calcific aortic valve disease. Background: Aortic stenosis (AS) is a chronic disorder characterized by pathological mineralization and remodelling. Studies have highlighted that human AS tissues are infiltrated by lipids and that inflammation may play a role into the pathobiology. We hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2/ PLA2G7) is expressed in AS and plays a role in the mineralization of valve interstitial cells (VICs). METHODS: We have documented the expression of phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. mRNA and protein expression were confirmed in aortic valves explanted from 60 patients by q-PCR and immunohistochemistry, respectively. The effect of lysophosphatidylcholine (LPC), the product of Lp-PLA2 activity, was documented on the mineralization of VIC cultures. RESULTS: Transcriptomic analyses of AS and control non-mineralized aortic valves revealed that Lp-PLA2 was increased by 4.2folds in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by q-PCR, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indices of tissue remodelling. In vitro, LPC increased the mRNA expression of alkaline phosphatase, ENPP1, Pit-1 and osteopontin. We then showed that LPC-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a PKA-dependent pathway. CONCLUSION: These results demonstrated that Lp-PLA2 is highly expressed in AS and plays a role in the mineralization of VICs.
Archives of Cardiovascular Diseases, 2008
Journal of Clinical & Experimental Cardiology, 2011
Background: Fetuin A is a circulating calcium-regulatory glycoprotein that inhibits ectopic and v... more Background: Fetuin A is a circulating calcium-regulatory glycoprotein that inhibits ectopic and vascular calcification. Aortic stenosis (AS) is a disease process involving an active calcification of the aortic valve (AV). Its prevalence increases markedly with aging. We examined the associations between serum level of Fetuin A with AV calcification, and disease progression rate of AS, in function of age. Methods: 226 patients operated for AS, were divided into 2 groups according to the median value of age: the younger group (<70 years) and the elderly group (≥70 years). Serum fetuin A levels and calcium content of AV were determined respectively by Elisa method and 0-cresolphtalein complexone method. The annualized progression rate of AS was calculated for the subset of patients (n=113) in whom at least 2 transthoracic Doppler-echocardiographic exams separated by at least 6 months were available pre-operatively. Results: There was no correlation between fetuin A level and AV calcium content or AS progression rate in the subset of younger patients. On the other hand, in the elderly group, the preoperative progression rate of the peak transvalvular gradient was 2-fold faster in patients with serum fetuin A level <0.36 g/L (median value) when compared to those with higher level of fetuin A (9±1 mmHg/year vs. 5±1 mmHg/year, p=0.02). Moreover, there was a negative correlation between calcium content of the AV explanted at the time of surgery and fetuin A serum level (r=-0.22, p=0.05). After adjusting for age, male gender, triglycerides and the morphology of the AV (bicuspid vs. tricuspid), fetuin A remained significantly and inversely associated with AV calcification (r 2 =0.09, β=-67.5, p= 0.04) and AS progression rate (r²=0.30, β=-10.4, p=0.02). Conclusion: In the elderly patients, reduced level of Fetuin A is associated with enhanced valvular calcification and faster stenosis progression rate. These findings also support that the determinants and mechanisms of the progression of AS may be different in younger patients.
European Journal of Clinical Investigation, 2011
Background Experimental and clinical studies have suggested that inhibitors of the renin angioten... more Background Experimental and clinical studies have suggested that inhibitors of the renin angiotensin system (RAS) might be useful to slow the progression of valvular calcification in patients with aortic stenosis (AS). Objectives The aim of this study was to evaluate the relationships between the weight and tissue remodelling score of stenotic aortic valves explanted at the time of valve replacement surgery and to determine the effect of medications including angiotensin II receptor type I blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors on these variables. Methods Aortic valve and blood plasma were collected in 208 patients with AS (mean age: 69 ± 9) who underwent aortic valve replacement. Valves were weighed and the degree of valve tissue remodelling was assessed using a modified scoring system from Warren (Score: 1-4). Also, the 0-cresolphtalein complexone method was used to measure the amount of calcium within the valve cusps. Results The mean weight of aortic valves was higher in men than in women (2AE83 ± 0AE09 vs. 1AE91 ± 0AE09 g, P < 0AE0001), in patients with bicuspid vs. tricuspid valves (3AE21 ± 0AE15 vs. 2AE23 ± 0AE07 g, P < 0AE0001), and in patients with higher remodelling score (score 2: 1AE86 ± 0AE19 g; score 3: 2AE08 ± 0AE12 g; score 4: 3AE08 ± 0AE1 g, P < 0AE0001). The remodelling score was higher in men (3AE35 ± 0AE05 vs. 2AE94 ± 0AE07, P < 0AE0001) and in bicuspid valves (3AE38 ± 0AE07 vs. 3AE14 ± 0AE05, P = 0AE006). Both valve weight (r = 0AE44, P < 0AE0001) and remodelling score (r = 0AE23, P = 0AE002) correlated with calcium content within the aortic valve. Patients under ARBs medication (n = 47, 22AE6%) had lower aortic valve weights (2AE14 ± 0AE13 g vs. 2AE63 ± 0AE09 g, P = 0AE001) and remodelling scores (3AE01 ± 0AE09 vs. 3AE26 ± 0AE04, P = 0AE009). On multivariate analyses, ARBs were significantly associated with a lower aortic valve remodelling score (P = 0AE04) and weight (P = 0AE02). Conclusions ARBs were associated with lower aortic valve weight and less pronounced tissue remodelling. Further studies are needed to determine if ARBs could be used as a therapeutic avenue in AS.
European Heart Journal, 2009
Introduction We recently demonstrated that metabolic syndrome (MetS) is an independent risk facto... more Introduction We recently demonstrated that metabolic syndrome (MetS) is an independent risk factor for postoperative atrial fibrillation (POAF) following coronary artery bypass grafting (CABG). In the present work, we sought to determine which feature of the MetS is associated with POAF. Methods and results We retrospectively analysed the association between metabolic features and the incidence of new-onset POAF in a total of 2214 male patients ,65 years who underwent first isolated CABG. Anthropometric data including waist circumference (WC) and complete preoperative lipid profile were available. We also conducted a nested case-control substudy including 147 patients who developed POAF, and were matched for age with a control population. In these patients, C-reactive protein, interleukin-6 (IL-6), and thiobarbituric acid-reactive substances (TBARS; evaluating the oxidative stress) blood levels were determined. In the whole cohort, 19.6% of patients developed POAF. On univariate analysis, body mass index (BMI; P ¼ 0.002) and WC (P ¼ 0.001) were the only anthropometric variables significantly associated with increased incidence of POAF. In the multivariable logistic model, the only independent predictors of POAF were a WC. 102 cm [odds ratio (OR) ¼ 1.40, P ¼ 0.04)] and older age (OR ¼ 1.08, P , 0.001). In the nested case-control substudy C-reactive protein, IL-6, and TBARS levels were not significantly different in patients with or without POAF. Of particular significance, patients with elevated WC. 102 cm and C-reactive protein. 1.5 mg/L or IL-6 .2.2 pg/mL were at a high risk of developing POAF (respectively, OR ¼ 2.32, P ¼ 0.02 and OR ¼ 2.27, P ¼ 0.03). Conclusion Patients with increased WC combined with elevated C-reactive protein levels are at higher risk for POAF. Thus, interventions targeting inflammation related to visceral obesity might help reducing the incidence of POAF.
PLoS ONE, 2011
Mémoire présenté à la Faculté des études supérieures de l"Université Laval dans le cadre du progr... more Mémoire présenté à la Faculté des études supérieures de l"Université Laval dans le cadre du programme de maîtrise en biologie cellulaire et moléculaire pour l"obtention du grade de maître ès sciences (M.Sc.
PLoS ONE, 2013
The regulation of phosphate (Pi) handling is crucial during calcification of the aortic valve. Ge... more 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 nonmineralized aortic valves. Treatment of VIC culture with Pi promoted the loss of mitochondrial membrane potential (DYm) 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.
Journal of the American College of Cardiology, 2014
This study sought to document the presence and role of lipoprotein-associated phospholipase A2 (L... more 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. (J Am Coll Cardiol 2014;63:460-9) ª 2014 by the American College of Cardiology Foundation Calcific aortic valve disease (CAVD) is a chronic and multifactorial disorder, which is characterized by an abnormal mineralization of aortic leaflets (1). Processes leading to the ectopic mineralization of the valvular tissue may involve lipid-derived factors (2,3). Phospholipase A2 (PLA2), encoded by the PLAG family of genes, are important enzymes that hydrolyze See page 478
Circulation: Cardiovascular Genetics, 2009
Background— Calcific aortic valve stenosis (AS) is a major societal and economic burden that is r... more 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 chai...
Canadian Journal of Cardiology, 2013
Arteriosclerosis, thrombosis, and vascular biology, 2014
This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricula... more 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. When compared with nondiabetic LDLr(-/-)/ApoB(100/100), diabetic LDLr(-/-)/ApoB(100/100)/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(-/-)/ApoB(100/100)/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr(-/-)/ApoB(100/100) mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr(-/-)/ApoB(100/100)/IGF-II mice when compared with LDLr(-/-)/ApoB(100/100). Importantly, we found that peak aortic jet velocity was significantly increased in LDLr(-/-)/ApoB(100/100)/IGF-II mice versus LDL...
An unusual case of involvement of Porphyromonas gingivalis is described. Two anaerobic isolates, ... more An unusual case of involvement of Porphyromonas gingivalis is described. Two anaerobic isolates, identified as Fusobacterium nucleatum and P. gingivalis, were recovered from the pus of a tubal-ovarian abscess in a 35-year-old woman. Identification of the P. gingivalis isolate was confirmed by randomly amplified polymorphic DNA fingerprinting.
A new species, Porphyromonas gulae sp. nov., is proposed to include strains isolated from the gin... more A new species, Porphyromonas gulae sp. nov., is proposed to include strains isolated from the gingival sulcus of various animal hosts which are distinct from related strains of Porphyromonas gingivalis of human origin. This bacterium exhibits the following characteristics : black-pigmented colonies ; asaccharolytic, obligate anaerobic growth ; and Gram-negative, non-motile and non-spore-forming, rod-shaped cells. Colonies do not fluoresce under UV light. Vitamin K 1 and haemin are required for growth. Cells haemagglutinate sheep erythrocytes. Major fatty acid end products are butyric acid, isovaleric acid, succinic acid and phenylacetic acid. Strains are catalase-positive and indole is produced. Alkaline phosphatase, trypsin-like and N-acetyl-β-glucosaminidase activities are strong. A β-galactosidase and a glutamylglutamic acid arylamidase are also present. The GMC content of the chromosomal DNA is 51 mol %. DNA-DNA homology data and 16S rRNA gene sequence analysis provide strong evidence that strains from the animal biotype of P. gingivalis represent a Porphyromonas species that is distinct from P. gingivalis. The type strain of P. gulae is Loup 1 T (l ATCC 51700 T l NCTC 13180 T ).
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Papers by Dominique Fournier