Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute contractility impairment due to dysbalance of calcium homeostasis

ABSTRACT: 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 at lower doses only the β5 proteasome subunit, whereas they differ in co-inhibition of other proteasome subunits at the higher doses: BTZ co-inhibits β1 subunit, whereas CFZ co- inhibits β2 subunit. This different pattern of inhibition affects differently the degree of functional proteasome inhibition with β5+β2 showing more effective 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 β5+β2 proteasome subunit inhibition, in contrast to the BTZ-type β5+β1 inhibition, directly interferes with cardiomyocyte contractility in vitro and in vivo. For the in vivo analysis, we used 6-8 weeks old Balb/c mice that were exposed to the drugs for 1h and subsequently euthanized. The hearts were processed for LC/MS-MS analysis. The hearts from CFZ-treated mice for 1h show showed impaired accumulation of proteins related to calcium handling (Atp2a2) and retinoid pathway (Aldh1a1), which is prevented by atRA (1 mg/kg) co-treatment. Our data suggests a novel mechanism for PI-induced cardiotoxicity that reflects clinical findings in which CFZ-type β5+β2 proteasome inhibition, in contrast to β5+β1 co-inhibition of BTZ, directly interferes with the contractile activity of cardiomyocytes.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Lenka Besse  

LAB HEAD: Lenka Besse

PROVIDER: PXD041167 | Pride | 2025-08-12

REPOSITORIES: Pride