Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F25%3A00142233" target="_blank" >RIV/00216224:14110/25:00142233 - isvavai.cz</a>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Carfilzomib-specific proteasome β5/β2 inhibition drives cardiotoxicity via remodeling of protein homeostasis and the renin-angiotensin-system

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

iScience

ISSN

2589-0042

e-ISSN

2589-0042

Svazek periodika

28

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

24

Strana od-do

1-24

Kód UT WoS článku

001581155100002

EID výsledku v databázi Scopus

2-s2.0-105013597106