Desmin modifications associate with amyloid-like oligomers deposition in heart failure

Giulio Agnetti, Victoria L. Halperin, Jonathan A. Kirk, Khalid Chakir, Yurong Guo, Linda Lund, Francesco Nicolini, Tiziano Gherli, Carlo Guarnieri, Claudio M. Caldarera, Gordon F. Tomaselli, David A. Kass, Jennifer E. Van Eyk

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

AimsThe ultimate cause of heart failure (HF) is not known to date. The cytoskeletal protein desmin is differentially modified and forms amyloid-like oligomers in HF. We postulated that desmin post-translational modifications (PTMs) could drive aberrant desmin aggregation in HF. Therefore, we identified these PTMs and investigated their impact on desmin amyloidogenicity in human and experimental HF.Methods and resultsWe detected increased levels of selectively phosphorylated and cleaved desmin in a canine pacing model of dyssynchronous HF (DHF) compared with either controls or animals treated with cardiac resynchronization therapy (CRT). This unique animal model combines clinically relevant features with the possibility of a partly rescued phenotype. We confirmed analogous changes in desmin modifications in human HF and identified two phosphorylation sites within a glycogen synthase kinase 3 (GSK3) consensus sequence. Desmin-positive oligomers were also increased in DHF hearts compared with controls. Their amyloid properties were decreased by treatment with CRT or an anti-amyloid small molecule. Finally, we confirmed GSK3's involvement with desmin phosphorylation using an in vitro model.ConclusionsBased on these findings, we postulate a new mechanism of cardiac toxicity based on the PTM-driven accumulation of desmin amyloid-like oligomers. Phosphorylation and cleavage as well as oligomers formation are reduced by treatment (CRT) indicating a relationship between the three. Finally, the decrease of desmin amyloid-like oligomers with CRT or small molecules points both to a general mechanism of HF based on desmin toxicity that is independent of protein mutations and to novel potential therapies.

Original languageEnglish (US)
Pages (from-to)24-34
Number of pages11
JournalCardiovascular research
Volume102
Issue number1
DOIs
StatePublished - Apr 2014
Externally publishedYes

Keywords

  • Amyloid
  • Desmin
  • Heart failure
  • Post-translational modifications
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Desmin modifications associate with amyloid-like oligomers deposition in heart failure'. Together they form a unique fingerprint.

  • Cite this

    Agnetti, G., Halperin, V. L., Kirk, J. A., Chakir, K., Guo, Y., Lund, L., Nicolini, F., Gherli, T., Guarnieri, C., Caldarera, C. M., Tomaselli, G. F., Kass, D. A., & Van Eyk, J. E. (2014). Desmin modifications associate with amyloid-like oligomers deposition in heart failure. Cardiovascular research, 102(1), 24-34. https://doi.org/10.1093/cvr/cvu003