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Cardiomyocyte-fibroblast interaction regulates ferroptosis and fibrosis after myocardial injury.

Mary E Mohr | Shuang Li | Allison M Trouten | Rebecca A Stairley | Patrick L Roddy | Chun Liu | Min Zhang | Henry M Sucov | Ge Tao
iScience | 2024

Neonatal mouse hearts have transient renewal capacity, which is lost in juvenile and adult stages. In neonatal mouse hearts, myocardial infarction (MI) causes an initial loss of cardiomyocytes. However, it is unclear which type of regulated cell death (RCD) occurs in stressed cardiomyocytes. In the current studies, we induced MI in neonatal and juvenile mouse hearts and showed that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrated that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine effects and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. The fibrogenic activity of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.

Pubmed ID: 38469561 RIS Download

Research resources used in this publication

Antibodies used in this publication

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM132055
  • Agency: NIGMS NIH HHS, United States
    Id: P20 GM103499
  • Agency: NIGMS NIH HHS, United States
    Id: R25 GM113278
  • Agency: NIGMS NIH HHS, United States
    Id: R25 GM072643
  • Agency: NHLBI NIH HHS, United States
    Id: T32 HL007260
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL148728
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL144938

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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R Project for Statistical Computing (tool)

RRID:SCR_001905

Software environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.

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Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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Proteintech Group (tool)

RRID:SCR_008986

Proteintech Europe Ltd is an ISO 9001:2008 certified company

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FISHER (tool)

RRID:SCR_009181

THIS RESOURCE IS NO LONGER IN SERVICE, documented on February 1st, 2022. Software application for genetic analysis of classical biometric traits like blood pressure or height that are caused by a combination of polygenic inheritance and complex environmental forces. (entry from Genetic Analysis Software)

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Abcam (tool)

RRID:SCR_012931

A commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.

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New England Biolabs (tool)

RRID:SCR_013517

An Antibody supplier

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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ThermoFisher Scientific EVOS M5000 Imaging System (tool)

RRID:SCR_023650

Microsoft system includes integrated digital inverted benchtop microscope for four-color fluorescence, transmitted-light, and color imaging. Provides interchangeable optics with autofocus, single-click multi-channel image acquisition.3.2 Megapixels, monochrome, CMOS camera. Offers software for acquisition, analysis, and automated cell counting.

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Recombinant Anti-Ferritin Heavy Chain antibody [EPR18878] (antibody)

RRID:AB_2940987

This recombinant monoclonal targets Ferritin Heavy Chain

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Goat anti-Mouse IgG (H+L) Secondary Antibody, HRP (antibody)

RRID:AB_1185566

This polyclonal secondary targets IgG (H+L)

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anti-Pitx2ABC (antibody)

RRID:AB_2819162

This polyclonal targets Pitx2ABC

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Donkey Anti-Goat IgG (H+L) Antibody, Alexa Fluor® 633 Conjugated (antibody)

RRID:AB_10562400

This unknown targets Donkey Goat IgG (H+L) Alexa Fluor® 633

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ACSL4 Polyclonal Antibody (antibody)

RRID:AB_2544613

This unknown targets ACSL4

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GPX4 antibody (antibody)

RRID:AB_2909469

This monoclonal targets GPX4

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Cardiac Troponin T Monoclonal Antibody (13-11) (antibody)

RRID:AB_11000742

This monoclonal targets Cardiac Troponin T

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CXCR2 Polyclonal Antibody (antibody)

RRID:AB_2790369

This unknown targets CXCR2

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FITC anti-mouse CD182 (CXCR2) (antibody)

RRID:AB_2566148

This monoclonal targets CD182

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ferritin heavy chain (B-12) (antibody)

RRID:AB_11150859

This monoclonal targets ferritin heavy chain (B-12)

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Thrombospondin antibody (antibody)

RRID:AB_10674322

This polyclonal targets Thrombospondin antibody

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Vimentin antibody [EPR3776] (antibody)

RRID:AB_10562134

This monoclonal targets Vimentin antibody [EPR3776]

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Mouse PDGF R alpha Antibody (antibody)

RRID:AB_2236897

This polyclonal targets Mouse PDGF R alpha

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Anti-Connexin 45 / GJA7 / Cx45 Antibody (antibody)

RRID:AB_2753195

This polyclonal targets Connexin 45/ GJA7/ Cx45

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Ferritin Light Chain antibody [EPR5260] (antibody)

RRID:AB_10862715

This monoclonal targets Ferritin Light Chain antibody [EPR5260]

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Anti-TGF beta Receptor II antibody (antibody)

RRID:AB_2728775

This polyclonal targets TGF beta Receptor II

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Anti-Smad2 (phospho S255) antibody (antibody)

RRID:AB_2732791

This monoclonal targets phospho-smad2

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Recombinant Anti-Smad3 (phospho S423 + S425) antibody [EP823Y] (antibody)

RRID:AB_882596

This recombinant monoclonal targets Smad3 (phospho S423 + S425)

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Monoclonal Anti-Actin, alpha-Smooth Muscle - Cy3(TM) antibody produced in mouse (antibody)

RRID:AB_476856

This monoclonal targets Actin alpha-Smooth Muscle - Cy3(TM) antibody produced in mouse

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COX2/ Cyclooxygenase 2/ PTGS2 antibody (antibody)

RRID:AB_2085127

This polyclonal targets COX2/ Cyclooxygenase 2/ PTGS2

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4 Hydroxynonenal Polyclonal Antibody (antibody)

RRID:AB_2827741

This polyclonal targets 4 Hydroxynonenal

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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STAR (software resource)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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STAR (software resource)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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RRID:IMSR_JAX:007676

Mus musculus with name B6.129(Cg)-Gt(ROSA)26Sortm4(ACTB-tdTomato.-EGFP)Luo/J from IMSR.

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B6.129(Cg)-Gt(ROSA)26Sortm4(ACTB-tdTomato.-EGFP)Luo/J (organism)

RRID:IMSR_JAX:007676

Mus musculus with name B6.129(Cg)-Gt(ROSA)26Sortm4(ACTB-tdTomato.-EGFP)Luo/J from IMSR.

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B6.129S-Postntm2.1(cre/Esr1*)Jmol/J (organism)

RRID:IMSR_JAX:029645

Mus musculus with name B6.129S-Postntm2.1(cre/Esr1*)Jmol/J from IMSR.

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B6.129S-Postntm2.1(cre/Esr1*)Jmol/J (organism)

RRID:IMSR_JAX:029645

Mus musculus with name B6.129S-Postntm2.1(cre/Esr1*)Jmol/J from IMSR.

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B6.129P2-Gt(ROSA)26Sortm1(DTA)Lky/J (organism)

RRID:IMSR_JAX:009669

Mus musculus with name B6.129P2-Gt(ROSA)26Sortm1(DTA)Lky/J from IMSR.

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B6.129P2-Gt(ROSA)26Sortm1(DTA)Lky/J (organism)

RRID:IMSR_JAX:009669

Mus musculus with name B6.129P2-Gt(ROSA)26Sortm1(DTA)Lky/J from IMSR.

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B6.129S-Pdgfratm1.1(cre/ERT2)Blh/J (organism)

RRID:IMSR_JAX:032770

Mus musculus with name B6.129S-Pdgfratm1.1(cre/ERT2)Blh/J from IMSR.

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B6.129S-Pdgfratm1.1(cre/ERT2)Blh/J (organism)

RRID:IMSR_JAX:032770

Mus musculus with name B6.129S-Pdgfratm1.1(cre/ERT2)Blh/J from IMSR.

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B6.FVB(129)-A1cfTg(Myh6-cre/Esr1*)1Jmk/J (organism)

RRID:IMSR_JAX:005657

Mus musculus with name B6.FVB(129)-A1cfTg(Myh6-cre/Esr1*)1Jmk/J from IMSR.

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B6.FVB(129)-A1cfTg(Myh6-cre/Esr1*)1Jmk/J (organism)

RRID:IMSR_JAX:005657

Mus musculus with name B6.FVB(129)-A1cfTg(Myh6-cre/Esr1*)1Jmk/J from IMSR.

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C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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FVB/NJ (organism)

RRID:IMSR_JAX:001800

Mus musculus with name FVB/NJ from IMSR.

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FVB/NJ (organism)

RRID:IMSR_JAX:001800

Mus musculus with name FVB/NJ from IMSR.

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WTC-mEGFP-TTN-cl39 (cell line)

RRID:CVCL_UD16

Cell line WTC-mEGFP-TTN-cl39 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)

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WTC-mEGFP-TTN-cl39 (cell line)

RRID:CVCL_UD16

Cell line WTC-mEGFP-TTN-cl39 is a Induced pluripotent stem cell with a species of origin Homo sapiens (Human)

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AC16 [Human hybrid cardiomyocyte] (cell line)

RRID:CVCL_4U18

Cell line AC16 [Human hybrid cardiomyocyte] is a Hybrid cell line with a species of origin Homo sapiens (Human)

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HEK293 (cell line)

RRID:CVCL_0045

Cell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)

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AC16 [Human hybrid cardiomyocyte] (cell line)

RRID:CVCL_4U18

Cell line AC16 [Human hybrid cardiomyocyte] is a Hybrid cell line with a species of origin Homo sapiens (Human)

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HEK293 (cell line)

RRID:CVCL_0045

Cell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)

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Recombinant Anti-Ferritin Heavy Chain antibody [EPR18878] (antibody)

RRID:AB_2940987

This recombinant monoclonal targets Ferritin Heavy Chain

View all literature mentions

Goat anti-Mouse IgG (H+L) Secondary Antibody, HRP (antibody)

RRID:AB_1185566

This polyclonal secondary targets IgG (H+L)

View all literature mentions

anti-Pitx2ABC (antibody)

RRID:AB_2819162

This polyclonal targets Pitx2ABC

View all literature mentions

Donkey Anti-Goat IgG (H+L) Antibody, Alexa Fluor® 633 Conjugated (antibody)

RRID:AB_10562400

This unknown targets Donkey Goat IgG (H+L) Alexa Fluor® 633

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ACSL4 Polyclonal Antibody (antibody)

RRID:AB_2544613

This unknown targets ACSL4

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GPX4 antibody (antibody)

RRID:AB_2909469

This monoclonal targets GPX4

View all literature mentions

Cardiac Troponin T Monoclonal Antibody (13-11) (antibody)

RRID:AB_11000742

This monoclonal targets Cardiac Troponin T

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CXCR2 Polyclonal Antibody (antibody)

RRID:AB_2790369

This unknown targets CXCR2

View all literature mentions

FITC anti-mouse CD182 (CXCR2) (antibody)

RRID:AB_2566148

This monoclonal targets CD182

View all literature mentions

ferritin heavy chain (B-12) (antibody)

RRID:AB_11150859

This monoclonal targets ferritin heavy chain (B-12)

View all literature mentions

Thrombospondin antibody (antibody)

RRID:AB_10674322

This polyclonal targets Thrombospondin antibody

View all literature mentions

Vimentin antibody [EPR3776] (antibody)

RRID:AB_10562134

This monoclonal targets Vimentin antibody [EPR3776]

View all literature mentions

Mouse PDGF R alpha Antibody (antibody)

RRID:AB_2236897

This polyclonal targets Mouse PDGF R alpha

View all literature mentions

Anti-Connexin 45 / GJA7 / Cx45 Antibody (antibody)

RRID:AB_2753195

This polyclonal targets Connexin 45/ GJA7/ Cx45

View all literature mentions

Ferritin Light Chain antibody [EPR5260] (antibody)

RRID:AB_10862715

This monoclonal targets Ferritin Light Chain antibody [EPR5260]

View all literature mentions

Anti-TGF beta Receptor II antibody (antibody)

RRID:AB_2728775

This polyclonal targets TGF beta Receptor II

View all literature mentions

Anti-Smad2 (phospho S255) antibody (antibody)

RRID:AB_2732791

This monoclonal targets phospho-smad2

View all literature mentions

Recombinant Anti-Smad3 (phospho S423 + S425) antibody [EP823Y] (antibody)

RRID:AB_882596

This recombinant monoclonal targets Smad3 (phospho S423 + S425)

View all literature mentions

Monoclonal Anti-Actin, alpha-Smooth Muscle - Cy3(TM) antibody produced in mouse (antibody)

RRID:AB_476856

This monoclonal targets Actin alpha-Smooth Muscle - Cy3(TM) antibody produced in mouse

View all literature mentions

COX2/ Cyclooxygenase 2/ PTGS2 antibody (antibody)

RRID:AB_2085127

This polyclonal targets COX2/ Cyclooxygenase 2/ PTGS2

View all literature mentions

4 Hydroxynonenal Polyclonal Antibody (antibody)

RRID:AB_2827741

This polyclonal targets 4 Hydroxynonenal

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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