Peter P Rainer1,2, Peihong Dong2, Matteo Sorge3, Justyna Fert-Bober4, Ronald J Holewinski4, Yuchuan Wang2, Catherine A Foss2, Steven S An5, Alessandra Baracca6, Giancarlo Solaini6, Charles G Glabe7, Martin G Pomper2, Jennifer E Van Eyk4, Gordon F Tomaselli2, Nazareno Paolocci2,8, Giulio Agnetti9,6. 1. From the Division of Cardiology, Medical University of Graz, Austria (P.P.R.). 2. Johns Hopkins School of Medicine, Baltimore, MD (P.P.R., P.D., Y.W., C.A.F., M.G.P., G.F.T., N.P., G.A.). 3. University of Turin, Italy (M.S.). 4. Cedars-Sinai Medical Center, Beverly-Hills, CA (J.F.-B., R.J.H., J.E.V.E.). 5. Johns Hopkins School of Public Health, Baltimore, MD (S.S.A.). 6. Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy (A.B., G.S., G.A.). 7. University of California Irvine (C.G.G.). 8. University of Perugia, Italy (N.P.). 9. Johns Hopkins School of Medicine, Baltimore, MD (P.P.R., P.D., Y.W., C.A.F., M.G.P., G.F.T., N.P., G.A.) gagnett1@jhmi.edu.
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.
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 humanischemic 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.
Authors: Steven R Houser; Kenneth B Margulies; Anne M Murphy; Francis G Spinale; Gary S Francis; Sumanth D Prabhu; Howard A Rockman; David A Kass; Jeffery D Molkentin; Mark A Sussman; Walter J Koch; Walter Koch Journal: Circ Res Date: 2012-05-17 Impact factor: 17.367
Authors: Khaushik Subramanian; Davide Gianni; Cristina Balla; Gabriele Egidy Assenza; Mugdha Joshi; Marc J Semigran; Thomas E Macgillivray; Jennifer E Van Eyk; Giulio Agnetti; Nazareno Paolocci; James R Bamburg; Pankaj B Agrawal; Federica Del Monte Journal: J Am Coll Cardiol Date: 2015-03-31 Impact factor: 24.094
Authors: Tatiana N Sidorova; Lisa C Mace; K Sam Wells; Liudmila V Yermalitskaya; Pei-Fang Su; Yu Shyr; John G Byrne; Michael R Petracek; James P Greelish; Steven J Hoff; Stephen K Ball; Charles G Glabe; Nancy J Brown; Joey V Barnett; Katherine T Murray Journal: J Histochem Cytochem Date: 2014-04-30 Impact factor: 2.479
Authors: Davide Gianni; Airong Li; Giuseppina Tesco; Kenneth M McKay; John Moore; Kunal Raygor; Marcello Rota; Judith K Gwathmey; G William Dec; Thomas Aretz; Annarosa Leri; Marc J Semigran; Piero Anversa; Thomas E Macgillivray; Rudolph E Tanzi; Federica del Monte Journal: Circulation Date: 2010-03-01 Impact factor: 29.690
Authors: Julie Heffler; Parisha P Shah; Patrick Robison; Sai Phyo; Kimberly Veliz; Keita Uchida; Alexey Bogush; Joshua Rhoades; Rajan Jain; Benjamin L Prosser Journal: Circ Res Date: 2019-12-11 Impact factor: 17.367
Authors: Hanming Zhang; Bo Pan; Penglong Wu; Nirmal Parajuli; Mark D Rekhter; Alfred L Goldberg; Xuejun Wang Journal: Sci Adv Date: 2019-05-22 Impact factor: 14.136
Authors: Maen D Abou Ziki; Neha Bhat; Arpita Neogi; Tristan P Driscoll; Nelson Ugwu; Ya Liu; Emily Smith; Johny M Abboud; Salah Chouairi; Martin A Schwartz; Joseph G Akar; Arya Mani Journal: Hum Mutat Date: 2021-07-29 Impact factor: 4.700