Theranostics 2022; 12(11):5237-5257. doi:10.7150/thno.70884 This issue Cite

Research Paper

Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging

Edoardo Lazzarini1#, Alessandra Maria Lodrini2,3#, Martina Arici2, Sara Bolis1,4, Sara Vagni2, Stefano Panella1, Azucena Rendon-Angel1,6, Melissa Saibene7, Alessia Metallo2, Tiziano Torre5, Giuseppe Vassalli4,6, Pietro Ameri8,9, Claudia Altomare1*, Marcella Rocchetti2✉*, Lucio Barile1,6,10✉*

1. Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
2. Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy.
3. Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
4. Cellular and Molecular Cardiology, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
5. Department of Cardiac Surgery Istituto Cardiocentro Ticino, Ente Ospedaliero Cantonale, Lugano, Switzerland.
6. Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
7. Department of Earth and Environmental Sciences, Università degli Studi di Milano-Bicocca, Milano, Italy.
8. Cardiovascular Disease Unit, IRCCS Ospedale Policlinico, Genova, Italy.
9. Department of Internal Medicine, University of Genova, Genova, Italy.
10. Institute of Life Science, Scuola Superiore Sant'Anna, Pisa, Italy.
# The first two Authors contributed equally to the study, authors are listed in alphabetical order.
*These authors are senior authors

Citation:
Lazzarini E, Lodrini AM, Arici M, Bolis S, Vagni S, Panella S, Rendon-Angel A, Saibene M, Metallo A, Torre T, Vassalli G, Ameri P, Altomare C, Rocchetti M, Barile L. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics 2022; 12(11):5237-5257. doi:10.7150/thno.70884. https://www.thno.org/v12p5237.htm
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Abstract

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Rationale: Aging in the heart is a gradual process, involving continuous changes in cardiovascular cells, including cardiomyocytes (CMs), namely cellular senescence. These changes finally lead to adverse organ remodeling and resulting in heart failure. This study exploits CMs from human induced pluripotent stem cells (iCMs) as a tool to model and characterize mechanisms involved in aging.

Methods and Results: Human somatic cells were reprogrammed into human induced pluripotent stem cells and subsequently differentiated in iCMs. A senescent-like phenotype (SenCMs) was induced by short exposure (3 hours) to doxorubicin (Dox) at the sub-lethal concentration of 0.2 µM. Dox treatment induced expression of cyclin-dependent kinase inhibitors p21 and p16, and increased positivity to senescence-associated beta-galactosidase when compared to untreated iCMs. SenCMs showed increased oxidative stress, alteration in mitochondrial morphology and depolarized mitochondrial membrane potential, which resulted in decreased ATP production. Functionally, when compared to iCMs, SenCMs showed, prolonged multicellular QTc and single cell APD, with increased APD variability and delayed afterdepolarizations (DADs) incidence, two well-known arrhythmogenic indexes. These effects were largely ascribable to augmented late sodium current (INaL) and reduced delayed rectifier potassium current (Ikr). Moreover sarcoplasmic reticulum (SR) Ca2+ content was reduced because of downregulated SERCA2 and increased RyR2-mediated Ca2+ leak. Electrical and intracellular Ca2+ alterations were mostly justified by increased CaMKII activity in SenCMs. Finally, SenCMs phenotype was furtherly confirmed by analyzing physiological aging in CMs isolated from old mice in comparison to young ones.

Conclusions: Overall, we showed that SenCMs recapitulate the phenotype of aged primary CMs in terms of senescence markers, electrical and Ca2+ handling properties and metabolic features. Thus, Dox-induced SenCMs can be considered a novel in vitro platform to study aging mechanisms and to envision cardiac specific anti-aging approach in humans.

Keywords: Induced pluripotent stem cell-derived cardiomyocytes, senescence, aging, heart


Citation styles

APA
Lazzarini, E., Lodrini, A.M., Arici, M., Bolis, S., Vagni, S., Panella, S., Rendon-Angel, A., Saibene, M., Metallo, A., Torre, T., Vassalli, G., Ameri, P., Altomare, C., Rocchetti, M., Barile, L. (2022). Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics, 12(11), 5237-5257. https://doi.org/10.7150/thno.70884.

ACS
Lazzarini, E.; Lodrini, A.M.; Arici, M.; Bolis, S.; Vagni, S.; Panella, S.; Rendon-Angel, A.; Saibene, M.; Metallo, A.; Torre, T.; Vassalli, G.; Ameri, P.; Altomare, C.; Rocchetti, M.; Barile, L. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics 2022, 12 (11), 5237-5257. DOI: 10.7150/thno.70884.

NLM
Lazzarini E, Lodrini AM, Arici M, Bolis S, Vagni S, Panella S, Rendon-Angel A, Saibene M, Metallo A, Torre T, Vassalli G, Ameri P, Altomare C, Rocchetti M, Barile L. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics 2022; 12(11):5237-5257. doi:10.7150/thno.70884. https://www.thno.org/v12p5237.htm

CSE
Lazzarini E, Lodrini AM, Arici M, Bolis S, Vagni S, Panella S, Rendon-Angel A, Saibene M, Metallo A, Torre T, Vassalli G, Ameri P, Altomare C, Rocchetti M, Barile L. 2022. Stress-induced premature senescence is associated with a prolonged QT interval and recapitulates features of cardiac aging. Theranostics. 12(11):5237-5257.

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