Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F25%3A00082411" target="_blank" >RIV/00159816:_____/25:00082411 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S2589004225014890" target="_blank" >https://www.sciencedirect.com/science/article/pii/S2589004225014890</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.isci.2025.113228" target="_blank" >10.1016/j.isci.2025.113228</a>
Alternative languages
Result language
angličtina
Original language name
Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system
Original language description
Compared to bortezomib treatment, multiple myeloma (MM) treatment with the proteasome inhibitor carfilzomib is associated with a higher incidence of cardiovascular adverse events. However, the mechanism underlying such cardiopathogenic side effects in MM patients remains elusive. Here, we show that carfilzomib-specific proteasome inhibition profoundly impairs cardiomyocyte contractility. Using an unbiased multiomics approach in vitro and in vivo, followed by in vitro validation, we elucidated carfilzomib-related changes in contractility proteins and cellular translation, retinol oxidative metabolism, and the angiotensin II derivative, angiotensin A. Subsequently, all-trans retinoic acid and angiotensin II type 1 receptor inhibitor prevented cardiomyocytes from experiencing carfilzomib-induced toxicity in human and murine in vitro and in vivo models through stabilization of protein and metabolic homeostasis. Our data reveal a mechanism underlying carfilzomib-induced cardiotoxicity that closely mirrors clinical observations and may open new avenues for management of such potentially lethal side effects in patients with MM.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30100 - Basic medicine
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
iScience
ISSN
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e-ISSN
2589-0042
Volume of the periodical
28
Issue of the periodical within the volume
9
Country of publishing house
US - UNITED STATES
Number of pages
24
Pages from-to
113228
UT code for WoS article
001581155100002
EID of the result in the Scopus database
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