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

33 Citations (Scopus)

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 - Jan 1 2014
Externally publishedYes

Fingerprint

Desmin
Amyloid
Heart Failure
Cardiac Resynchronization Therapy
Post Translational Protein Processing
Phosphorylation
Glycogen Synthase Kinase 3
Cytoskeletal Proteins
Consensus Sequence
Canidae
Therapeutics
Animal Models
Phenotype

Keywords

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

ASJC Scopus subject areas

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

Cite this

Agnetti, G., Halperin, V. L., Kirk, J. A., Chakir, K., Guo, Y., Lund, L., ... 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

Desmin modifications associate with amyloid-like oligomers deposition in heart failure. / Agnetti, Giulio; Halperin, Victoria L.; Kirk, Jonathan A.; Chakir, Khalid; Guo, Yurong; Lund, Linda; Nicolini, Francesco; Gherli, Tiziano; Guarnieri, Carlo; Caldarera, Claudio M.; Tomaselli, Gordon F.; Kass, David A.; Van Eyk, Jennifer E.

In: Cardiovascular Research, Vol. 102, No. 1, 01.01.2014, p. 24-34.

Research output: Contribution to journalArticle

Agnetti, G, Halperin, VL, Kirk, JA, Chakir, K, Guo, Y, Lund, L, Nicolini, F, Gherli, T, Guarnieri, C, Caldarera, CM, Tomaselli, GF, Kass, DA & Van Eyk, JE 2014, 'Desmin modifications associate with amyloid-like oligomers deposition in heart failure', Cardiovascular Research, vol. 102, no. 1, pp. 24-34. https://doi.org/10.1093/cvr/cvu003
Agnetti, Giulio ; Halperin, Victoria L. ; Kirk, Jonathan A. ; Chakir, Khalid ; Guo, Yurong ; Lund, Linda ; Nicolini, Francesco ; Gherli, Tiziano ; Guarnieri, Carlo ; Caldarera, Claudio M. ; Tomaselli, Gordon F. ; Kass, David A. ; Van Eyk, Jennifer E. / Desmin modifications associate with amyloid-like oligomers deposition in heart failure. In: Cardiovascular Research. 2014 ; Vol. 102, No. 1. pp. 24-34.
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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.",
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AU - Halperin, Victoria L.

AU - Kirk, Jonathan A.

AU - Chakir, Khalid

AU - Guo, Yurong

AU - Lund, Linda

AU - Nicolini, Francesco

AU - Gherli, Tiziano

AU - Guarnieri, Carlo

AU - Caldarera, Claudio M.

AU - Tomaselli, Gordon F.

AU - Kass, David A.

AU - Van Eyk, Jennifer E.

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Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Amyloid

KW - Desmin

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KW - Post-translational modifications

KW - Proteomics

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