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Gustav Smith, MD, PhD

Gustav Smith

Associate professor

Gustav Smith, MD, PhD

Analysis of genetic variant associated with heart failure mortality implicates thymic stromal lymphopoietin as mediator of strain-induced myocardial fibroblast-mast cell crosstalk and fibrosis

Author

  • Neha Pimpalwar
  • Selvi Celik
  • Mardjaneh Karbalaei Sadegh
  • Tomasz Czuba
  • Olof Gidlöf
  • J. Gustav Smith

Summary, in English

Heart failure (HF) is a leading cause of death and disability globally. Heritable factors and the extent and pattern of myocardial fibrosis are important determinants of outcomes in patients with HF. In a genome-wide association study of mortality in HF, we recently identified a genetic polymorphism on chromosome 5q22 associated with HF mortality. Here, we sought to study the mechanisms by which this variant may influence myocardial disease processes. We find that the risk allele is located in an enhancer motif upstream of the TSLP gene (encoding thymic stromal lymphopoietin), conferring increased binding of the transcription factor nescient helix–loop helix 1 (NHLH1) and increased TSLP expression in human heart. Further, we find that increased strain of primary human myocardial fibroblasts results in increased TSLP expression and that the TSLP receptor is expressed in myocardial mast cells in human single nuclei RNA sequence data. Finally, we show that TSLP overexpression induces increased transforming growth factor β expression in myocardial mast cells and tissue fibrosis. Collectively, our findings based on follow-up of a human genetic finding implicate a novel pathway in myocardial tissue homeostasis and remodeling.

Department/s

  • Cardiology
  • Molecular Epidemiology and Cardiology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Cardiovascular Epigenetics
  • Molecular Cardiology
  • WCMM-Wallenberg Centre for Molecular Medicine
  • Heart Failure and Mechanical Support
  • EpiHealth: Epidemiology for Health

Publishing year

2024-02

Language

English

Publication/Series

FASEB Journal

Volume

38

Issue

4

Document type

Journal article

Publisher

Wiley

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • cardiomyopathy
  • fibroblasts
  • fibrosis
  • heart failure
  • mast cells
  • tslp

Status

Published

Research group

  • Molecular Epidemiology and Cardiology
  • Cardiovascular Epigenetics
  • Molecular Cardiology
  • Heart Failure and Mechanical Support

ISBN/ISSN/Other

  • ISSN: 0892-6638