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Transcriptome Analysis Identifies Proteostasis and Cell Survival Pathway Disruption in Peripartum Cardiomyopathy, Leading to Heart Failure

ABSTRACT: Peripartum cardiomyopathy (PPCM) is a pregnancy-associated form of systolic heart failure that develops when hemodynamic, metabolic, and hormonal stress of late gestation exceeds maternal cardiac adaptive capacity. While vascular, inflammatory, and genetic contributions have been implicated in PPCM, the integrated molecular programs connecting pregnancy-related stress to cardiomyocyte failure remain poorly defined. To elucidate these mechanisms, we performed a transcriptome-wide RNA seq of left ventricles from females with PPCM and non-failing female normal donor controls. Differential expression analysis identified 2891 genes with altered expressions (1491 upregulated, 1400 downregulated; fold change ≥ 2, FDR < 0.05). Ingenuity pathway analysis (IPA) revealed the activation of protein ubiquitination pathways, EIF2 signaling, mitochondrial dysfunction, and apoptosis pathways. Upstream regulator analysis indicated the suppression of mitochondrial protease CLPP (Z = −4.075) and activation of COPS5 (Z = +5.982) and TEAD1 (Z = +5.00), delineating dual regulatory modules of disease remodeling. Integrated network analysis demonstrated a loss of protein quality control and survival signaling with the activation of stress response and translational repression programs. This signifies a collapse of proteostasis and maladaptive adaptation. Collectively, these data define PPCM as a disorder of failed proteostasis and impaired translational homeostasis. Our analysis provides a systems-level framework connecting PPCM to ventricular dysfunction with potential therapeutic targets in mitochondria, protein quality-control, integrated stress–response, and COP9 signaling pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335944 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Metabolic challenges experienced by dairy cows during the transition between pregnancy and lactation (also known as peripartum), are of considerable interest from a nutrigenomic perspective. The mobilization of large amounts of non-esterified fatty acids (NEFA) leads to an increase in NEFA uptake in the liver, the excess of which can cause hepatic accumulation of lipids and ultimately fatty liver. Interestingly, peripartum NEFA activate the peroxisome proliferator-activated receptor (PPAR), a transcriptional regulator with known nutrigenomic properties. The study of PPAR activation in the liver of periparturient dairy cows is thus crucial; however, current in vitro models of the bovine liver are inadequate, and the isolation of primary hepatocytes is prohibitive and error-prone. The objective of the current study was to evaluate the use of precision-cut liver slices (PCLS) from liver biopsies as a model for PPAR activation in periparturient dairy cows. Four cows were enrolled in the experiment, and PCLS from each were prepared prepartum (-10 DIM) and postpartum (+10 DIM) and treated with a variety of PPAR agonists and antagonist. Gene expression was assayed through RT-qPCR and RNAseq, and intracellular triglyceride concentration was measured. PCLS treated with PPARγ agonist rosiglitazone displayed upregulation of canonical PPAR targets ACADVL and LIPC in the postpartum, while a PPARδ agonists increased expression of PPAR target PDK4; no gene expression changes were detected in the prepartum, and triglyceride concentrations were unchanged between treatments. Transcriptome sequencing revealed considerable differences in response to PPAR agonist, mainly related to pathways involved with lipid metabolism and the immune response. Among differentially expressed genes, a subset of 91 genes were identified as novel putative PPAR targets in the bovine liver, by cross-referencing our results with a publicly-available dataset of predicted PPAR target genes, and supplementing our finding with prior literature. Our results provide important insights on the use of PCLS as a model for assaying PPAR activation in the peripartum.

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Transcriptome Analysis Identifies Proteostasis and Cell Survival Pathway Disruption in Peripartum Cardiomyopathy, Leading to Heart Failure

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