Project description:In order to better understand the molecular mechanisms underlying right ventricular failure in human PAH, a RNA sequencing analysis was performed in RV tissues obtained from subjects clinically categorized as compensated RV (n=11), decompensated RV (n=7) and donor controls (n=14). The study unveils a plethora of factors dysregulated in the RV of PAH patients, which opens new perspectives for translational research.
Project description:14 days after a single subcutaneous monocrotaline (MCT) injection we isolated the left and right ventricles from wistar rats. Factor1: Comparison between control (CON), compensated hypertrophy (HYP), and decompensated hypertrophy (CHF). Factor2: Comparison between left ventricle (LV) and right ventricle (RV). Keywords: dose response
Project description:The molecular mechanisms of progressive right heart failure are incompletely understood. We systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signatures, protein, and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes (including proenkephalin) and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans
Project description:Left and right heart ventricles of adult male mice were profiled to determine the differences in gene expression, control, coordination and signaling fabrics Two-sides (L= left, R = right) gene expression profiling experiment in adult mouse male (M) ventricles (V). 4 biological replicates: MVL1-4, MVR1-4.
Project description:We recently introduced a modification of the established monocrotaline (MCT) model for pulmonary hypertension (PH) and subsequent right ventricular (RV) hypertrophy, which allows for the selective induction of either a compensate or decompensated RV hypertrophic phenotype within four weeks after a single subcutaneous MCT injection. Both doses of 30 or 80 mg/kg body weight lead to an intermediate phase of compensated RV hypertrophy (day 14-19), while the former dose leads to a stable compensated phenotype (HYP) and the latter dose progresses towards decompensated ventricular hypertrophy and RV failure (CHF) around day 25-28 (Buermans et. al, Physiological Genomics 2005). This model provides the unique opportunity to characterize the development of either hypertrophic phenotype during the very early stages after imposition of RV pressure overload remodeling, well before phenotypical differences have become apparent. This experiment series describes gene expression profiles, generated by spotted oligonucleotide microarrays, to characterize and compare the expression of ~4800 genes from the RV of HYP, CHF and time matched control rats at 10, 19 and 25 days after injections. RV samples were hybridized against a common reference pool, prepared from total RNA isolated from the interventricular septum wall from animals at day 19 and 25. Keywords: dose response x time course
Project description:Left and right heart ventricles of adult male mice were profiled to determine the differences in gene expression, control, coordination and signaling fabrics
Project description:We performed molecular phenotyping of RV remodeling, using transcriptome analysis of RV tissue obtained from MCT-induced rats (of both male and female animals). The clustering approach along with precise hemodynamics assessments identified “early" and "late" subgroups of decompensated state in rat RV. Further molecular characterization of these subgroups identified distinct molecular genes and pathways within different stages of RV remodeling. This study provided a resource to comprehensively compare human RV remodeling with the current animal model of PH (MCT), and led to validation of state-specific biomarkers and potential therapeutic targets for RV dysfunction.
Project description:Heart failure (HF), a major health concern worldwide, with high morbidity and mortality, renders the urgent need for new treatments. Lingguizhugan decoction (LD), a classic Chinese formula, has been clinically used to treat HF. However, the molecular mechanisms involved are not fully elucidated. In this study, we first used the experimental model of transverse aortic constriction (TAC)-induced HF in C57BL/6J mice to evaluate the therapeutic efficacy of LD. Our results showed that LD exerted protective effects against TAC-induced HF by alleviating cardiac dysfunction and cardiac dilation, which might be associated with LD’s effects on down-regulating CH-related gene and protein expression. To further reveal the potential molecular mechanisms of LD in the treatment of HF, we utilized the network pharmacology to predict the core targets and potential pathways and further utilized the transcriptomics to provide changed gene profile in the heart tissue. Our results suggested that cardiac hypertrophy signaling including AKT and MAPKs signaling pathways were significantly enriched, indicating that these pathways may be the major regulatory for LD on HF treatment. Furthermore, the protein levels in AKT-GSK3β/mTOR and MAPKs pathway were determined in both compensated and decompensated states. LD inhibited the MAPKs activation, especially, reducing phosphorylated levels of p38 from the compensated state and phosphorylated levels of ERK from the decompensated state, and the latter might depend on the regulation of AMPK by LD. Moreover, LD exerts a dual role in regulating AKT-GSK3β/mTOR/P70S6K signaling pathway, characterized by active effects in the compensated state, and inhibitory effects in the decompensated state. The regulatory effect of LD on mTOR might rely on activating AKT in the compensatory state, while might be jointly determined by AKT and AMPKαin the decompensated state. Finally, by using UPLC-QE-MS/MS analysis, we detected 62 compounds in LD extract, and found 19 of which were detected in plasma of rats. Among them, 17 bioactive compounds likely regulate AKT-GSK3β/mTOR and MAPKs signaling pathway by using bioinformatics prediction. Taken together, our study showed that LD did have a better therapeutic effect on HF via dynamically balancing AKT-GSK3β/mTOR/P70S6K pathway and MAPKs pathway. Moreover, our study also provides possible bioactive compounds responsible for LD treatment on HF.
Project description:In this study, we performed molecular phenotyping of RV remodeling, by transcriptome analysis of RV tissue obtained from 40 patients. The unsupervised clustering analysis identified “early" and "late" subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, and different circulating levels of several ECM proteins in decompensated RV subgroups. Our study provides a resource for the subphenotyping of RV states, the identification of state-specific biomarkers, and potential therapeutic targets for RV dysfunction.