Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca(2+) levels, and Ca(2+) cycling. The altered intracellular Ca(2+) cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes / Sartiani, Laura; Bucciantini, Monica; Spinelli, Valentina; Leri, Manuela; Natalello, Antonino; Nosi, Daniele; Maria Doglia, Silvia; Relini, Annalisa; Penco, Amanda; Giorgetti, Sofia; Gerace, Elisabetta; Mannaioni, Guido; Bellotti, Vittorio; Rigacci, Stefania; Cerbai, Elisabetta; Stefani, Massimo. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - STAMPA. - 111:(2016), pp. 2024-2038. [10.1016/j.bpj.2016.09.010]

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

SARTIANI, LAURA;BUCCIANTINI, MONICA;SPINELLI, VALENTINA;LERI, MANUELA;NOSI, DANIELE;GERACE, ELISABETTA;MANNAIONI, GUIDO;RIGACCI, STEFANIA;CERBAI, ELISABETTA;STEFANI, MASSIMO
2016

Abstract

Transthyretin (TTR) amyloidoses are familial or sporadic degenerative conditions that often feature heavy cardiac involvement. Presently, no effective pharmacological therapy for TTR amyloidoses is available, mostly due to a substantial lack of knowledge about both the molecular mechanisms of TTR aggregation in tissue and the ensuing functional and viability modifications that occur in aggregate-exposed cells. TTR amyloidoses are of particular interest regarding the relation between functional and viability impairment in aggregate-exposed excitable cells such as peripheral neurons and cardiomyocytes. In particular, the latter cells provide an opportunity to investigate in parallel the electrophysiological and biochemical modifications that take place when the cells are exposed for various lengths of time to variously aggregated wild-type TTR, a condition that characterizes senile systemic amyloidosis. In this study, we investigated biochemical and electrophysiological modifications in cardiomyocytes exposed to amyloid oligomers or fibrils of wild-type TTR or to its T4-stabilized form, which resists tetramer disassembly, misfolding, and aggregation. Amyloid TTR cytotoxicity results in mitochondrial potential modification, oxidative stress, deregulation of cytoplasmic Ca(2+) levels, and Ca(2+) cycling. The altered intracellular Ca(2+) cycling causes a prolongation of the action potential, as determined by whole-cell recordings of action potentials on isolated mouse ventricular myocytes, which may contribute to the development of cellular arrhythmias and conduction alterations often seen in patients with TTR amyloidosis. Our data add information about the biochemical, functional, and viability alterations that occur in cardiomyocytes exposed to aggregated TTR, and provide clues as to the molecular and physiological basis of heart dysfunction in sporadic senile systemic amyloidosis and familial amyloid cardiomyopathy forms of TTR amyloidoses.
2016
111
2024
2038
Sartiani, Laura; Bucciantini, Monica; Spinelli, Valentina; Leri, Manuela; Natalello, Antonino; Nosi, Daniele; Maria Doglia, Silvia; Relini, Annalisa; Penco, Amanda; Giorgetti, Sofia; Gerace, Elisabetta; Mannaioni, Guido; Bellotti, Vittorio; Rigacci, Stefania; Cerbai, Elisabetta; Stefani, Massimo
File in questo prodotto:
File Dimensione Formato  
2016 Biochemical and Electrophysiological Modification Sartiani et al.pdf

accesso aperto

Tipologia: Versione finale referata (Postprint, Accepted manuscript)
Licenza: Tutti i diritti riservati
Dimensione 1.99 MB
Formato Adobe PDF
1.99 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1059024
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 18
social impact