Lactate Dehydrogenase B and Pyruvate Oxidation Pathway associated with Carfilzomib-Related Cardiotoxicity in Multiple Myeloma Patients: Result of a Multi-Omics Integrative Analysis
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood Plasma
SUBMITTER: 
Marwa Tantawy
LAB HEAD: Yan Gong
PROVIDER: PXD024281 | Pride | 2021-04-27
REPOSITORIES: Pride
Dataset's files
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| Yan-iTRAQ-1-1-1.raw | Raw | |||
| Yan-iTRAQ-1-1.raw | Raw | |||
| Yan-iTRAQ-1-10.raw | Raw | |||
| Yan-iTRAQ-1-11.raw | Raw | |||
| Yan-iTRAQ-1-12.raw | Raw |
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Project 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.
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Project description:Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome beta 5 (B5) subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ but is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We time to investigate the transcriptomic effects of acute proteasome inhibition in the murine heart.
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Project 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 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.
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Project description:Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.
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Project description:Carfilzomib (CFZ) is a proteasome inhibitor commonly used in the treatment of multiple myeloma, but its clinical application is limited due to its cardiotoxicity. The Neiguan acupoint (PC6) stimulation has been reported to effectively improve cardiac function, but its regulatory mechanism remains unclear. The aim of this study was to investigate the effect and underlying mechanism of electroacupuncture (EA) against CFZ-induced cardiotoxicity in C57BL/6 mice. According to our results, EA treatment significantly reversed CFZ-induced ejection fraction and fractional shortening reduction, which showed great potential effect for heart protection. By using RNA-sequencing, we compared the transcriptome profile of heart samples from DMSO control, CFZ injection, and EA treatment mice, and nearly 40,000,000 valid sequence reads aligned with 20,000 genes from six libraries were obtained. A total of 770 differentially expressed genes (DEGs) were identified in the CFZ (vs. Control) group, including 65 up-regulated and 705 down-regulated genes. Meanwhile, 329 DEGs were obtained in the EA (vs. CFZ) group, including 251 up-regulated and 78 down-regulated genes. Our results shed new insights into the regulatory mechanism of EA at PC6 against CFZ-induced cardiotoxicity, which could further provide theoretical basis for clinical EA therapy.
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