Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Molecular profiling of dilated cardiomyopathy that progresses to heart failure
Michael A. Burke, … , Jonathan G. Seidman, Christine E. Seidman
Michael A. Burke, … , Jonathan G. Seidman, Christine E. Seidman
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86898. https://doi.org/10.1172/jci.insight.86898.
View: Text | PDF
Research Article Cardiology

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

  • Text
  • PDF
Abstract

Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10–4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10–33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

Authors

Michael A. Burke, Stephen Chang, Hiroko Wakimoto, Joshua M. Gorham, David A. Conner, Danos C. Christodoulou, Michael G. Parfenov, Steve R. DePalma, Seda Eminaga, Tetsuo Konno, Jonathan G. Seidman, Christine E. Seidman

×

Figure 6

Downregulation of PPAR signaling in PLNR9C/+ with development of DCM.

Options: View larger image (or click on image) Download as PowerPoint
Downregulation of PPAR signaling in PLNR9C/+ with development of DCM.
(A...
(A) Upstream regulator analysis predicted transcription factors that were activated (gray, Z-score > 2) or inhibited (black, Z-score < –2) in PLNR9C/+ cardiomyocytes with DCM. (B) PPAR pathway genes and key cofactors were downregulated in PLNR9C/+ mice with development of DCM (*P < 0.001). Data plotted as natural log (ln) of fold-change (n = 3 mice pooled prior to RNA-seq). Bayesian P value corrected for multiple hypothesis testing (10). (C) PPARα and RXRα downregulation is predicted to affect a number of downstream metabolic pathways. Genes and pathways regulated by PPARα/RXRα that are downregulated (red) or upregulated (green) in PLNR9C/+ mice with DCM are highlighted. Dashed arrows indicate signaling networks not shown in detail. Adapted from Ingenuity canonical pathway PPARα/RXRα activation. †, representative cell surface receptors that signal to PPARα/RXRα.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts