PXD029077-1

PXD029077 is an original dataset announced via ProteomeXchange.

Title	Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute cardiomyocyte energy depletion and local angiotensin synthesis
Description	Treatment of multiple myeloma (MM) with the second-generation proteasome inhibitor (PI) carfilzomib (CFZ) is associated with higher incidence of cardiovascular adverse events compared to first-generation PI bortezomib (BTZ). CFZ and BTZ inhibit the individual proteasome subunits beta1, beta2 and beta5 differently, leading to changes in the degree of functional proteasome inhibition. It is unclear, whether CFZ-induced cardiotoxicity is the result of proteasome inhibition, or an off-target effect. With an unbiased multi-omics approach in conjunction with proteasome subunit-specific inhibitors, we show that CFZ-type 5+2 proteasome subunit inhibition, in contrast to the BTZ-type 5+1 inhibition, directly interferes with cardiomyocyte contractility in vitro and in vivo. CFZ-treated cardiomyocytes showed impaired accumulation of proteins related to ATP production and oxidative metabolism. Single-cell transcriptomic analysis of CFZ-treated murine hearts revealed cardiomyocyte-specific changes leading to impaired cardiac contraction. Metabolic profiling revealed increased levels of cardiac Angiotensin A and nucleoside depletion after CFZ treatment. Angiotensin II Type 1 receptor (AGT1R) inhibitors, all-trans retinoic acid (atRA) or supplementation of soluble amino acids rescued cardiomyocytes from CFZ-induced toxicity in human and murine models in vitro, while they ameliorated the cardiotoxic phenotype in vivo. Our data suggests a novel mechanism for PI-induced cardiotoxicity that reflects clinical findings in which CFZ-type 5+2 proteasome inhibition, in contrast to 5+1 co-inhibition of BTZ, directly interferes with the contractile activity of cardiomyocytes.
HostingRepository	PRIDE
AnnounceDate	2025-08-01
AnnouncementXML	Submission_2025-08-01_09:02:18.488.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bogdan Florea
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	MALDI Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-12 07:52:58	ID requested
⏵ 1	2025-08-01 09:02:18	announced

10.1016/J.ISCI.2025.113228;

submitter keyword: redox pathways, contractility, cardiomyocytes,Carfilzomib, energy metabolism, proteasome

Lenka Besse
contact affiliation	Laboratory for Experimental Hematology, St. Gallen Cantonal Hospital; St. Gallen, 9007, Switzerland
contact email	Lenka.Besse@kssg.ch
lab head
Bogdan Florea
contact affiliation	Leiden Institute for Chemistry
contact email	b.florea@chem.leidenuniv.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029077
     1. Label: PRIDE project
     2. Name: Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute cardiomyocyte energy depletion and local angiotensin synthesis