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Myocardial cellular gene expression during pressure overload: evidence for transient partial endothelial to mesenchymal transition [scDROP-seq]

ABSTRACT: Pathological processes underlying pressure overload triggered heart failure were mainly analyzed from a cardiomyocyte centric view. To identify new cellular mechanisms, we isolated cardiomyocytes, endothelial cells and fibroblasts as most abundant cardiac cell types from mice in the subacute and chronic stages of pressure overload (by transverse aortic constriction, TAC) and performed RNA-sequencing. We detected highly cell-type specific transcriptional responses with characteristic time courses and active intercellular communication, especially early after TAC. We focused on endothelial cells, and single-cell sequencing in this population showed enhanced expression of collagens and inflammatory mediators at this stage. Importantly, these endothelial transcriptional changes were transduced to the translational level as shown by Ribo-Tag sequencing and verification of collagen protein production by cardiac endothelial cells. In conclusion, we provide a resource of cardiac cellular gene expression in pressure overload and reveal the induction of collagens by endothelial cells as potential therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE180736 | GEO | 2022/02/08

REPOSITORIES: GEO

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Project description:Aims: Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload, and that Rho signaling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy. Methods and Results: Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10–12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy related genes, including immediate early genes (IEGs), in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the F/G-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors (MRTFs) and serum response factor (SRF) were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs. Conclusions: mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.

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Myocardial cellular gene expression during pressure overload: evidence for transient partial endothelial to mesenchymal transition [scDROP-seq]

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