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The transcriptome of mouse

ABSTRACT: Cumulative research demonstrated that heart muscles in the dilated cardiomyopathy (DCM) patients are marked by down-regulated expression of α-myosin heavy chain (α-MHC) coding by MYH6 while it remains unknown whether this reduction contributes to DCM. In our work, we proved that the expression level of α-MHC was decreased in the heart of DCM patients compared to that of non-failure donors. We established two Myh6 down-expressed Syrian Hamster models: one with α-MHC deficiency across all systems, the other with α-MHC knockdown specifically in the heart by using adeno-associatedvirus (AAV). Besides the animal models, we also programmed MYH6 knockout human-induced pluripotent stem cells (hiPSCs) which differentiated later into cardiomyocytes (hiPS-CMs) in vitro. We found α-MHC deficiency in vivo or in vitro both resulted in DCM phenotypes, meanwhile we demonstrated α-MHC deficiency is a causative factor of DCM. We also proved that the DCM-associated α-MHC deficiency was mediated by the autophagy flux. At the same time, the DCM phenotypes were attenuated by rapamycin, an autophagy activator, and exacerbated by inhibiting autophagic activities. Transcriptomic and proteomics results revealed that cardiomyocytes with α-MHC deficiency apparently exhibited actin cytoskeleton dysfunction. Our data demonstrated that α-MHC deficiency influenced the actin cytoskeleton network to regulate the autophagy activity suggesting that overexpress α-MHC or regulating autophagy would be a promising therapeutic candidate for DCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE241119 | GEO | 2024/08/16

REPOSITORIES: GEO

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The transcriptome of humans

Project description:Cumulative research demonstrated that heart muscles in the dilated cardiomyopathy (DCM) patients are marked by down-regulated expression of α-myosin heavy chain (α-MHC) coding by MYH6 while it remains unknown whether this reduction contributes to DCM. In our work, we proved that the expression level of α-MHC was decreased in the heart of DCM patients compared to that of non-failure donors. We established two Myh6 down-expressed Syrian Hamster models: one with α-MHC deficiency across all systems, the other with α-MHC knockdown specifically in the heart by using adeno-associatedvirus (AAV). Besides the animal models, we also programmed MYH6 knockout human-induced pluripotent stem cells (hiPSCs) which differentiated later into cardiomyocytes (hiPS-CMs) in vitro. We found α-MHC deficiency in vivo or in vitro both resulted in DCM phenotypes, meanwhile we demonstrated α-MHC deficiency is a causative factor of DCM. We also proved that the DCM-associated α-MHC deficiency was mediated by the autophagy flux. At the same time, the DCM phenotypes were attenuated by rapamycin, an autophagy activator, and exacerbated by inhibiting autophagic activities. Transcriptomic and proteomics results revealed that cardiomyocytes with α-MHC deficiency apparently exhibited actin cytoskeleton dysfunction. Our data demonstrated that α-MHC deficiency influenced the actin cytoskeleton network to regulate the autophagy activity suggesting that overexpress α-MHC or regulating autophagy would be a promising therapeutic candidate for DCM.

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Project description:About one third of dilated cardiomyopathy (DCM) cases are caused by mutations in sarcomere or cytoskeletal proteins. Yet treating the cytoskeleton directly is not possible because drugs that bind to actin are not well tolerated. Mutations in the actin binding protein CAP2 can cause DCM and knockout mice, either whole body (CAP2 KO) or cardiomyocyte specific knockouts (CAP2 CKO), develop DCM with cardiac conduction disease. RNA-seq analysis of CAP2 KO hearts and isolated cardiomyocytes revealed over-activation of fetal genes including serum response factor (SRF) regulated genes such as Myl9 and Acta2 prior to the emergence of cardiac disease. To test if we could treat CAP2 KO mice, we synthesized and tested the SRF inhibitor CCG-1423-8u. CCG-1423-8u reduced expression of the SRF targets Myl9 and Acta2, as well as the biomarker of heart failure, NPPA. The median survival of CAP2 CKO mice was 98 days, while CCG-1423-8u treated CKO mice survived for 116 days and also maintain normal cardiac function longer. These results suggest that some forms of sudden cardiac death and cardiac conduction disease are under cytoskeletal stress and that inhibiting signaling through SRF may benefit DCM by reducing cytoskeletal stress.

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