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

Circulation Research
Peter P RainerGiulio Agnetti

Abstract

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. 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. 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. Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to car...Continue Reading

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Citations

Jun 22, 2018·Biophysics Reviews·Andreas BrodehlHendrik Milting
Feb 26, 2020·Cells·Sonia R SinghGiulio Agnetti
Jun 7, 2019·Circulation Research·Ruth Williams, UNKNOWN Editors
May 12, 2018·Circulation Research·Sonia R Singh, Jeffrey Robbins
Sep 19, 2019·Current Medicinal Chemistry·Gianluca TestaCarlo G Tocchetti
Jul 22, 2018·Biophysics Reviews·Mary TsikitisYassemi Capetanaki
Jul 13, 2020·Heart Failure Reviews·Evelyn N LumngwenaNtobeko A B Ntusi
Mar 5, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Antonia T L ZechLucie Carrier
Aug 20, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Senem SalcanSebastian Kötter
Apr 8, 2021·The FEBS Journal·Giulio AgnettiShenhav Cohen

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