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Transcriptional profiling of male and female MCT-induced rats with compensated and decompensated right ventricle

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE240923 | GEO | 2023/09/29

REPOSITORIES: GEO

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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:Abstract: Right ventricular failure (RVF) remains the leading cause of death in pulmonary arterial hypertension (PAH). We investigated the transcriptomic signature of RVF in hemodynamically well-phenotyped monocrotaline (MCT)-treated, male, Sprague-Dawley rats with severe PAH and decompensated RVF (increased right ventricular (RV) end diastolic volume (EDV), decreased cardiac output (CO), tricuspid annular plane systolic excursion (TAPSE) and ventricular-arterial decoupling). RNA sequencing revealed 2547 differentially regulated transcripts in MCT-RVF RVs. Multiple enriched gene ontology (GO) terms converged on mitochondria/metabolism, fibrosis, inflammation, and angiogenesis. The mitochondrial transcriptomic pathway is the most affected in RVF, with 413 dysregulated genes. Downregulated genes included tfam (−0.45-fold), suggesting impaired mitochondrial biogenesis, Cyp2e1 (−3.8-fold), a monooxygenase which when downregulated increases oxidative stress, dehydrogenase/reductase 7C (Dhrs7c) (−2.8-fold), consistent with excessive autonomic activation, and polypeptide N-acetyl-galactose-aminyl-transferase 13 (Galnt13), a known pulmonary hypertension (PH) biomarker (−2.7-fold). The most up-regulated gene encodes Periostin (Postn; 4.5-fold), a matricellular protein relevant to fibrosis. Other dysregulated genes relevant to fibrosis include latent-transforming growth factor beta-binding protein 2 (Ltbp2), thrombospondin4 (Thbs4). We also identified one dysregulated gene relevant to all disordered transcriptomic pathways, Annexin A1. This anti-inflammatory, phospholipid-binding mediator, is a putative target for therapy in RVF-PAH. Comparison of expression profiles in the MCT-RV with published microarray data from the RV of pulmonary artery-banded mice and humans with bone morphogenetic protein receptor type 2 (BMPR2)-mutations PAH reveals substantial conservation of gene dysregulation, which may facilitate clinical translation of preclinical therapeutic and biomarkers studies. Transcriptomics reveals the molecular fingerprint of RVF to be heavily characterized by mitochondrial dysfunction, fibrosis and inflammation.

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Transcriptional profiling of male and female MCT-induced rats with compensated and decompensated right ventricle

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