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MRNA sequencing of control and resolvase-deficient ex vivo-stimulated B cells

ABSTRACT: Our RNA-seq analysis comparing control, Gen1-knockout, Mus81-knockout, and Gen1-Mus81-double knockout activated B cells showed that the control and Gen1-KO B lymphocytes resemble each other transcriptomically whereas differential gene expression (DGE) analysis comparing Mus81-KO to control cells identified 8 genes with a minimum of 2-fold upregulation in Mus81-KO cells. Between Gen1-KO and Mus81-KO cells, the transcript level of only 4 genes, including Mus81 were differentially altered. DGE analysis of control versus DKO cells, on the contrary, revealed that 279 genes were upregulated by at least twofold (log2 fold change 1; FDR <0.05) and 167 genes were downregulated by a minimum of log2 fold change of –0.3 in the DKO B cells (corresponding to a 19% de-enrichment relative to control cells).

ORGANISM(S): Mus musculus

PROVIDER: GSE195734 | GEO | 2022/02/01

REPOSITORIES: GEO

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Project description:Abstract Aim: Circulating triglyceride and triglyceride-rich lipoprotein (TRL) accumulation is increasingly recognized as a residual atherosclerotic risk, but their specific effect in cardiac remodeling and heart failure (HF) remain largely unexplored. Here we investigated this issue in Gpihbp1 knockout (KO) mice, which develop severe hyperchylomicronemia due to disruption of intravascular TRL hydrolysis . Methods: Cardiac lipid metabolism and remodeling were evaluated in 10-month-old Gpihbp1 KO mice and wild-type littermates under physiological conditions. Mice were also subjected to transverse aortic constriction (TAC) to evaluate the impact of severe hyperchylomicronemia on pressure overload-induced remodeling and HF. Furthermore, Gpihbp1 KO mice were crossed into Ldlr KO background to study hyperchylomicronemia’s effects on hemorheology and high-fat diet (HFD)-induced cardiac pathology. Results: Untargeted cardiac lipidomics revealed 214 differentially regulated lipid species specifically enriched in glycerophospholipids, fatty acid (FA) and diacylglycerol subclasses. qPCR confirmed down-regulated FA oxidation genes and upregulated glucose utilization genes. Electron microscopy showed swollen mitochondria with fragmented cristae, and RNA-seq demonstrated reduced respiratory-chain gene expression. These derangements culminated in impaired cardiac contractile performance in 10-month-old Gpihbp1 KO mice without inducing hypertrophy or fibrosis. After TAC, Gpihbp1 KO hearts exhibited exaggerated diastolic dysfunction, increased myocyte hypertrophy, and fibrosis. In Gpihbp1/Ldlr double knockout (dKO) mice, reduced erythrocyte deformability and increased whole blood viscosity were observed and worsened post-HFD. Additionally, HFD feeding precipitated significant diastolic impairment, cardiac hypertrophy and fibrosis in dKO mice. Conclusion: Severe hyperchylomicronemia due to GPIHBP1 deficiency sensitizes the heart to pathological remodeling and HF. These findings indicate a potential pathogenic contribution of HTG and TRL accumulation to cardiac disease.

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MRNA sequencing of control and resolvase-deficient ex vivo-stimulated B cells

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