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Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure.
- Source :
-
Circulation research [Circ Res] 2018 May 11; Vol. 122 (10), pp. e75-e83. Date of Electronic Publication: 2018 Feb 26. - Publication Year :
- 2018
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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.<br />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.<br />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.<br />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.<br /> (© 2018 American Heart Association, Inc.)
- Subjects :
- Amyloid analysis
Amyloid drug effects
Animals
Catechin analogs & derivatives
Catechin pharmacology
Cells, Cultured
Desmin genetics
Female
Genetic Vectors
Heart Failure etiology
Humans
Male
Mass Spectrometry methods
Mice
Mice, Knockout
Mutagenesis, Site-Directed
Myocardial Ischemia complications
Phosphorylation
Polymorphism, Single Nucleotide
Positron-Emission Tomography methods
Pressure
Protein Aggregates drug effects
Protein Folding
Rats
Recombinant Proteins metabolism
alpha-Crystallins deficiency
beta-Crystallins deficiency
Amyloid metabolism
Desmin metabolism
Heart Failure metabolism
Myocytes, Cardiac metabolism
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 122
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 29483093
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.117.312082