Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure

Peter P. Rainer, Peihong Dong, Matteo Sorge, Justyna Fert-Bober, Ronald J. Holewinski, Yuchuan Wang, Catherine A. Foss, Steven S. An, Alessandra Baracca, Giancarlo Solaini, Charles G. Glabe, Martin G. Pomper, Jennifer E. Van Eyk, Gordon F. Tomaselli, Nazareno Paolocci, Giulio Agnetti

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

RATIONALE: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. OBJECTIVE: We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF. METHODS AND RESULTS: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF. CONCLUSIONS: Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF.

Original languageEnglish (US)
Pages (from-to)e75-e83
JournalCirculation research
Volume122
Issue number10
DOIs
StatePublished - May 11 2018
Externally publishedYes

Keywords

  • amyloid
  • desmin
  • heart failure
  • phosphorylation
  • proteostasis

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Rainer, P. P., Dong, P., Sorge, M., Fert-Bober, J., Holewinski, R. J., Wang, Y., Foss, C. A., An, S. S., Baracca, A., Solaini, G., Glabe, C. G., Pomper, M. G., Van Eyk, J. E., Tomaselli, G. F., Paolocci, N., & Agnetti, G. (2018). Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure. Circulation research, 122(10), e75-e83. https://doi.org/10.1161/CIRCRESAHA.117.312082