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bioRxiv · 10.1101/2023.06.21.546019

Cardiomyocytes Deficiency of SENP1 Promotes Myocardial Fibrosis via Paracrine Action

Liu, Z.
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Abstract

BackgroundSENP1 (Sentrin-specific protease 1) is involved in heart disease by regulating intracellular SUMOylation. However, the role of cell type-specific SENP1 in the setting of myocardial infarction (MI) remains to be defined. We determined whether cardiomyocyte-specific SENP1 regulates maladaptive remodeling in the ischemic heart. MethodsWe generated cardiomyocyte-specific SENP1 knockout and overexpression mice to assess cardiac function and ventricular remodeling responses under physiological and pathological conditions. Adult mouse cardiomyocytes and fibroblasts were separated to observe the paracrine effects of cardiomyocytes. DIA proteomic assay and bioinformatic analysis were performed to detect differential proteins in primary cardiomyocytes. Single-cell sequencing data were analyzed to identify key cardiomyocyte cluster regulated by SENP1 after MI. Mass spectrometry was performed to search for key effector proteins regulated by SENP1. ResultsSENP1 expression reduced in post-infarction mice and patients with heart failure. Cardiomyocyte-specific SENP1 deficiency (genetic or adeno-associated virus (AAV)-mediated) triggered a myocardial fibrotic response and progressive cardiac dysfunction. MI exacerbated the poor ventricular remodeling response mediated by SENP1 deletion, SENP1 overexpression improved cardiac function and reduced fibrosis. Further, we found that increased cardiac fibrosis in the cardiomyocyte-specific SENP1 deletion mice, associated with increased Fn expression and secretion in cardiomyocytes, promoted fibroblast activation in response to myocardial injury. Mechanistically, SENP promoted deSUMOylation of the HSP90ab1 (heat shock protein 90 alpha, class B, member 1) Lys72 and ubiquitin-dependent degradation, which reduced HSP90ab1-mediated phosphorylation of STAT3 (signal transducer and activator of transcription 3) and transcriptional activation of Fn, and then reduced fibroblast activation in the indirect coculture model. On the other hand, AAV-mediated mutation of the HSP90ab1 Lys72 ameliorated adverse ventricular remodeling and dysfunction post-MI. ConclusionsSENP1 is essential for repressing STAT3-mediated Fn transcription by regulating deSUMOylation of HSP90ab1. Blockade of HSP90ab1 SUMOylation at the Lys72 site is a novel therapy effective in reversing adverse ventricular remodeling post-MI. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/546019v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@18199c9org.highwire.dtl.DTLVardef@1976105org.highwire.dtl.DTLVardef@162c56borg.highwire.dtl.DTLVardef@18f1d8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Liu, Z.. 2023-06-24. Cardiomyocytes Deficiency of SENP1 Promotes Myocardial Fibrosis via Paracrine Action. https://doi.org/10.1101/2023.06.21.546019

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