f5b52f55604016ad89cb84365fd5a0a1 328004.pdf bc494c13a907c1cef75c624c905b0369c9b12212 328004.pdf 78d31871254c21a6b51f0863c11824f576fa3ddf7b8cbc816694e8264ed4a067 328004.pdf Title: Cardiac-Specific Overexpression of ERR in Mice Induces Severe Heart Dysfunction and Early Lethality Subject: Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERR or ERR results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERR, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERR, which die at young ages due to heart failure. ERR transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERR could play a role in mediating cardiac pathogenic responses. Keywords: cardiac dysfunction; estrogen-related receptors; transgenic mice Author: Jaime Lasheras, Rosario Pardo, Marc Velilla, Marcos Poncelas, Núria Salvatella, Rafael Simó, Marisol Ruiz-Meana, Mònica Zamora and Josep A. 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WinAnsi yes yes no 276 0 KODLKJ+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 279 0 KODLHG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 295 0 KODLKG+PalatinoLinotype CID TrueType Identity-H yes yes yes 298 0 KODLKH+PalatinoLinotype TrueType WinAnsi yes yes no 304 0 KODLKJ+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 307 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 320 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2026-04-29 04:19:36 CEST RepresentationInformation: 328004.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2026-04-28 13:53:59 CEST Size: 2808418 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 499 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Transgenic Mice with Cardiac-Specific Overexpression of ERR Show Premature Lethality Destination: subsection.2.1 Item: Title: Mice Overexpressing High Levels of ERR Exhibit Cardiac Functional Defects Destination: subsection.2.2 Item: Title: ERR Cardiac Overexpression Is Associated with Cardiomyocyte Hypertrophy, Apoptosis, Fibrosis, and Altered Gene Expression Destination: subsection.2.3 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Generation of Cardiac-Specific ERR Transgenic Mice Destination: subsection.4.1 Item: Title: Gene Expression Analysis Destination: subsection.4.2 Item: Title: Western Blot Destination: subsection.4.3 Item: Title: Histological Analysis Destination: subsection.4.4 Item: Title: Apoptosis Destination: subsection.4.5 Item: Title: Echocardiography Destination: subsection.4.6 Item: Title: Statistical Analysis Destination: subsection.4.7 Item: Title: References Destination: subsection.4.7 Info: Title: Cardiac-Specific Overexpression of ERR in Mice Induces Severe Heart Dysfunction and Early Lethality Author: Jaime Lasheras, Rosario Pardo, Marc Velilla, Marcos Poncelas, Núria Salvatella, Rafael Simó, Marisol Ruiz-Meana, Mònica Zamora and Josep A. Villena Subject: Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERR or ERR results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERR, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERR, which die at young ages due to heart failure. ERR transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERR could play a role in mediating cardiac pathogenic responses. 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