BBLN triggers CAMK2D pathology in mice under cardiac pressure overload and potentially in unrepaired hearts with tetralogy of Fallot

Joshua Abd Alla, Andreas Langer, Stefan Wolf, Xuebin Fu, Mohamed Abdelfattah Rageh, Ursula Quitterer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Tetralogy of Fallot (TOF) is one of the most prevalent congenital heart defects, with adverse cardiac remodeling and long-term cardiac complications. Here, searching for pathomechanisms, we find upregulated bublin coiled-coil protein (BBLN) in heart specimens of TOF patients with cyanosis, which positively correlates with cardiac remodeling pathways. Human BBLN, a protein with largely unknown function, promoted heart failure features, with increased mortality when overexpressed in mice, in a protein dosage-dependent manner. BBLN enhanced cardiac inflammation, fibrosis and necroptosis by calcium/calmodulin-dependent protein kinase II delta (CAMK2D) activation, whereas a BBLN mutant with impaired CAMK2D binding was inert. Downregulation of CAMK2D by an interfering RNA retarded BBLN-induced symptoms of heart failure. Endogenous BBLN was induced by hypoxia as a major TOF feature in human patients and by chronic pressure overload in mice, and its downregulation decreased CAMK2D hyperactivity, necroptosis and cardiovascular dysfunction. Thus, BBLN promotes CAMK2D-induced pathways to pathological cardiac remodeling, which are triggered by hypoxia in TOF.

Original languageEnglish (US)
Pages (from-to)1044-1059
Number of pages16
JournalNature Cardiovascular Research
Volume2
Issue number11
DOIs
StatePublished - Nov 2023

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology
  • Medicine (miscellaneous)
  • Cardiology and Cardiovascular Medicine

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