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Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes
- Publication Year :
- 2016
- Publisher :
- Biophysical Society, 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 Ca2+ levels, and Ca2+ cycling. The altered intracellular Ca2+ 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.
- Subjects :
- 0301 basic medicine
Amyloid
Cytoplasm
endocrine system
Heart Ventricles
Biophysics
FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA)
Nanotechnology
Protein aggregation
transgenic mice
Fibril
cellular death
Familial amyloid cardiomyopathy
Mice
Protein Aggregates
03 medical and health sciences
Aberrant protein oligomers
GM1 ganglioside
Alzheimer's disease
calcium influx
oxidative stress
action potential
atomic force microscopy
0302 clinical medicine
medicine
Animals
Humans
Prealbumin
Myocyte
Myocytes, Cardiac
Amyloid, Biophysics
biology
Chemistry
Amyloidosis
nutritional and metabolic diseases
medicine.disease
Electrophysiological Phenomena
Cell biology
Mice, Inbred C57BL
Transthyretin
030104 developmental biology
Cell Biophysics
biology.protein
Calcium
Transtiretina, Amiloidosi, Transthyretin, Amyloidosis
030217 neurology & neurosurgery
Intracellular
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....dd9e0f04f28f3ef6af079673b732c4c7