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Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute cardiomyocyte energy depletion and local angiotensin synthesis

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 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.

INSTRUMENT(S): MALDI Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Electrically Active Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Bogdan Florea

LAB HEAD: Lenka Besse

PROVIDER: PXD029077 | Pride | 2025-08-01

REPOSITORIES: Pride

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			Action	DRS
	20191008_MM_BTZ_01.zip.raw	Raw
	20191008_MM_BTZ_02.zip.raw	Raw
	20191008_MM_DMSO_01.zip.raw	Raw
	20191008_MM_DMSO_02.zip.raw	Raw
	20191008_MM__CFZ_01.zip.raw	Raw

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Project description:Carfilzomib has a good effect in treating multiple myeloma, but more and more clinical studies have shown that the drug can cause cardiac toxicity during use, but the mechanism of action is unclear. This study aimed to comprehensively elucidate the mechanism of CFZ-induced cardiomyopathy by constructing a C57BL/6 mouse model and combining cell experiments. The research results showed that the hearts of mice treated with CFZ appeared significantly enlarged, and the cardiac function indicators decreased. The serum enzyme LDH, AST, and CK-MB levels significantly increased, suggesting severe myocardial injury. RNA extraction and QPCR detection of the heart showed that the expression of heart hypertrophy and fibrosis markers increased. Meanwhile, histological staining found that there were fewer cardiomyocytes, damaged myofibrils, and cardiac fibrosis. In the cell experiments, CFZ treatment caused the release of more LDH from rat cardiomyocytes and H9C2 cells, increased CASPASE 3/7 activity, abnormal cell morphology, enlarged cell size, myocardial hypertrophy and fibrosis marker gene expression in cardiomyocytes. Through the study of the SUMOYLATION pathway, it was found that CFZ's effects on cardiomyocyte structure and function were related to the expression of SENP genes, especially SENP1, which showed a significant downregulation in cardiomyocytes and mouse heart tissue, and was positively correlated with the levels of cardiac injury marker genes. This study further explored the mechanism of action by specifically altering the expression of SENP1 in cardiomyocytes. The results show that the knockdown of SENP1 in cardiomyocytes leads to more severe myocardial damage after CFZ treatment, suggesting that the expression of SENP1 can potentially affect the cardiotoxicity caused by CFZ. Further, by using silver staining and mass spectrometry to identify the interacting proteins with SENP1 after CFZ treatment, we found that the knockdown of DDX17 had a similar myocardial injury effect as SENP1. Subsequently, through Co-IP, protein stability experiments, and ubiquitination analysis experiments, we determined that SENP1 can maintain the protein stability of DDX17 by inhibiting its SUMO modification, thereby preventing cardiomyocyte injury and apoptosis. We hope to provide a new perspective and potential cardioprotective strategy for clinical use.

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Proteasome beta2 and beta5 subunit inhibition by carfilzomib causes acute cardiomyocyte energy depletion and local angiotensin synthesis

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