Biology subjects

Bartoli-Leonard, F.

Publications and source records attributed to Bartoli-Leonard, F..

3 recordsLinked to original sources

bioRxiv2024

Sexual Dimorphism of Plasma and Tissue Proteomes in Human Calcific Aortic Valve Stenosis Pathogenesis

BACKGROUNDCalcific aortic valve stenosis (CAVS) is a global clinical burden, impacting around 2% of the population over 65 years of age. No pharmacotherapeutics exist, with surgical repair and transcatheter valve replacement being the only intervention. Females are underrepresented in studies of CAVS, leading to delay in timely intervention and increased mortality. Histopathology demonstrates female CAVS presents with decreased valvular calcification but increased fibrosis and severity of symptoms. We hypothesize that the underlying molecular mechanisms contributing to disease progression and fibrocalcific burden in AS differs between male and female patients. Our goal for this study is to use previously acquired proteomic datasets of a clinically-defined human AS cohort to examine sex disparities and underlying sex-specific disease signatures. METHODS and RESULTSAge-matched human AS tissue samples (n=4 females, n=14 males) were each segmented into non-diseased, fibrotic, and calcified disease stages and analyzed using LC-MS/MS proteomics and quantitative histopathology. CAVD plasma samples (n=20 females, n=30 males) were analyzed for circulating sex-specific biomarkers via LC-MS/MS. Unbiased principal component analysis shows sex- and stage-specific proteome clustering. AS pathogenesis drove sex-specific disparities in the valvular proteome: 338/1503 total proteins were differentially-enriched by sex across disease stages. Compared to sex-specific non-diseased controls, female fibrotic tissue resulted in 2.75-fold greater number of differentially-enriched proteins than did male fibrotic tissue (female: 42, male: 16; p<0.05 threshold). In contrast, female calcific tissue identified 2.473-fold less differentially-enriched proteins than male calcific tissue (female: 157, male 356; q<0.05 threshold). By Functional Enrichment Analysis revealed specific proteins responsible for the exacerbated valvular fibrosis signature in females, implicated adenosine phosphate metabolism as a potential male-specific driver of AS, and further reinforce the shared contribution of aberrant lipid and cholesterol activity to AS progression in both sexes. CONCLUSIONSWe reveal a sexually-dimorphic AS proteome, including the novel overabundance of ECM remodeling pathways in female calcified aortic valve tissues. This analysis allows for identification of potential sex-specific protein drug targets implicated in AS pathobiology.

pathology↗

bioRxiv2024

Altered inflammatory state and mitochondrial function identified by transcriptomics in paediatric congenital heart patients prior to surgical repair

ObjectiveCongenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor in sustained cardiac health in these patients, thus by elucidating divergent profiles between CHD and control through tissue analysis this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Approach & ResultsTranscriptomic profiling, in silico cellular deconvolution and functional network analysis was conducted on RV biopsies obtained from CHD and control paedatric patients. Analysis identified an increase in mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67E-132, 2.23E-107, respectively), Cytotoxic T cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, p = 0.0118, respectively) and proinflammatory marker Caspase1 (p=0.0055) in CHD compared to control. Gene set enrichment identified mitochondrial dysfunctional pathways, predominately changes to the oxidative phosphorylation processes. Negative regulation of mitochondrial functions and metabolism was identified in functional network analysis, with dysregulation of mitochondrial complex formation. Histological analysis confirmed an increase in cellular bodies with the CHD RV tissue, and positive staining for both CD45 and CD8 in CHD RV tissue, which was absent in control. Deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). Network analysis identified positive regulation of the immune system and cytokine signalling clusters within the inflammation functional network as were lymphocyte activation and leukocyte differentiation. ConclusionsUtilizing RV tissue from paediatric patients undergoing CHD cardiac surgery this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T cell presence prior to reparative surgery.

immunology↗

bioRxiv2023

Single-cell T cell receptor sequencing of paired tissue and blood samples reveals clonal expansion of CD8+ effector T cells in patients with calcific aortic valve disease

Calcific aortic valve disease (CAVD) is a complex cardiovascular pathology, culminating in aortic stenosis, heart failure and premature mortality, with no comprehensive treatment strategy, except valve replacement. While T cells have been identified within the valve, their contribution to pathogenesis remains unclear. To elucidate the heterogenous phenotype of the immune populations present within patients with CAVD, deep phenotypic screens of paired valve and peripheral blood cells were conducted via flow cytometry (n=20) and immunohistochemistry (n=10). Following identification of a significant population of memory T cells; specifically, CD8+ T cells within the valve, single cell RNA sequencing and paired single T cell receptor sequencing was conducted on a further 4 patients on CD45+ CD3+, CD4+ or CD8+ T cells. Through unsupervised clustering, 7 T cell populations were identified within the blood and 10 identified within the valve. Tissue resident memory (TRM) T cells were detected for the first time within the valve, exhibiting a highly cytotoxic, activated, and terminally differentiated phenotype. This pan-pro-inflammatory signal was differentially identified in T cells originating from the valve, and not observed in the blood, indicative of an adaptive, local not-systemic inflammatory signature in CAVD patients. T cell receptor analysis identified hyperexpanded clones within the CD8+ T cell central memory (TCM) population, with TRM cells comprising the majority of large and medium clonal expansion within the entire T cell population. Clonal interaction network analysis demonstrated the greatest proportion of clones originating from CD8+ T cell effector memory (TEM) and CD4+ naive / TCM populations and ending in the CD8+ TRM and CD8+ TCM clusters, suggesting a clonal expansion and predicted trajectory of T cells towards a tissue resident, cytotoxic environment within the valve. CDR3 epitope predictive analysis identified 7 potential epitope targets, of which GALNT4 and CR1L have previously been implicated in a cardiovascular context as mediators of inflammation. Taken together, the data identified T cell sub-populations within the context of CAVD and further predicted possible epitopes responsible for the clonal expansion of the valvular T cells, which may be important for propagating inflammation in CAVD.

immunology↗