Recurrent ventricular fibrillation with different tyrosine kinase inhibitors for chronic myeloid leukemia

Prashar, Abhisheik; Ilsar, Rahn; Roncolato, Fernando; Hopkins, A.

doi:10.1016/j.hrcr.2020.07.016

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…However, direct evidence to connect protein kinases activity and cardiac abnormalities is still lacking. On the other hand, several studies showed that TKIs-induced cellular oxidative stress and alterations in cardiac structure and contractions [53][54][55][56][57][58] , suggesting that the "cardiotoxicity" from TKI most likely result from both on-and offtarget effects.…”

Section: Discussionmentioning

confidence: 99%

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

Liu

Duren

et al. 2022

Preprint

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Tyrosine kinase inhibitors (TKIs) have been widely used for cancer chemotherapy, but they also cause cardiotoxicities in cancer patients. In this study, we used human stem cells as an in-vitro system to interrogate the mechanisms underlying drug-induced toxicity in differentiated cardiomyocytes, including anticancer tyrosine kinase inhibitor (TKI) drugs, including imatinib, sunitinib, and vandetanib. Sublethal TKI exposure produces multiple effects, including disarranged sarcomere structure, interrupted Ca2+-handling, and impaired mitochondrial function, evident of TKI-induced toxicity in differentiated cardiomyocytes. GATA4-mediated regulatory networks, including key mitochondrial target genes, emerge as significant molecular signatures in integrated analyses of transcriptome and chromatin accessibility dynamics. We find that, on a molecular level, GATA4 acts as a regulatory factor in mitochondrial biogenesis and OXPHOS by directly regulating specific metabolism-related genes, such as PPARGC1A. Functional genomic experiments targeting GATA4 reveals that GATA4 upregulation by CRISPR-activation is able to restore mitochondrial morphology and OXPHOS upon TKI exposure. In addition, we also identified that GATA4 is involved in regulation of mitochondrial biogenesis during early cardiac differentiation; inhibition of GATA4 during differentiation reduces mitochondrial DNA content, ATP production, and OXPHOS in differentiated cardiomyocytes, demonstrating a developmental role of GATA4 in metabolic management during early cardiac differentiation. Altogether, our study identifies a novel link between GATA4 and mitochondria in cardiomyocytes, and identifies GATA4 as a promising therapeutic target for reducing TKI-induced cardiotoxicity for human health.

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Section: Discussionmentioning

confidence: 99%

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

Liu

Duren

et al. 2022

Preprint

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“…And, both the PC tyrosine (TAT and TAC) kinases effect and angiotensin II-induced protection and are necessary for trigger mechanism of ischemic preconditioning [34]. And, the Src kinase activation mediates ischemic injury but triggers IPC in the position either upstream of or parallel to membrane associated PKC-ε [35].…”

Section: The Necessity Of Pyrimidine Kinases (Tat and Tac) In Acyl-co...mentioning

confidence: 99%

Pyrimidine TAT TAC Kinases Promote B- Arrestins And Rac1 For Adopting Myocardial Constrictions And GPCRs Ratio By Ang2-AT2 Synthesis And Anti-Inflammatory Growth

Tantawi¹

2022

Genesis

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The orphan nuclear pathway (regulated by pyrimidine TAT and TAC kinases and OPA1 enzymes) has the roles of producing the Beta-subunit (fatty Acyl-COA-beta) upon the effects of synthase which regulate B-arrestins synthesis for adopting ACE for Ang2-AT2 synthesis from Ang1-AT1 (that adopt GPCRs ratio). The inhibition in synthase and in pyrimidines kinases will reflect Inhibition in Acyl-COA-beta synthesis followed by cholesterol and long fatty chains accumulations with high affinity to bind with k and Na salts that can precipitated and cause lipotoxicity. B-arrestins play a well established role in the dampening of G-protein coupled receptors (GPCRs) accumulation, that prevent their increasing through its adopting to ACE for activating Ang2-AT2 synthesis from Ang1-AT1.

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Tyrosine kinase inhibitor–associated ventricular arrhythmias: a case series and review of literature

Fazal

Wei

Chuy

et al. 2022

J Interv Card Electrophysiol

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Recurrent ventricular fibrillation with different tyrosine kinase inhibitors for chronic myeloid leukemia

Cited by 5 publications

References 7 publications

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

GATA4 regulates mitochondrial biogenesis and functions during cardiac development and rescues cardiac and mitochondrial functions impaired by TKIs

Pyrimidine TAT TAC Kinases Promote B- Arrestins And Rac1 For Adopting Myocardial Constrictions And GPCRs Ratio By Ang2-AT2 Synthesis And Anti-Inflammatory Growth

Tyrosine kinase inhibitor–associated ventricular arrhythmias: a case series and review of literature

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