Pentraxin 3 regulates tyrosine kinase inhibitor-associated cardiomyocyte contraction and mitochondrial dysfunction via ERK/JNK signalling pathways - 08/12/22
, Ainun Nizar Masbuchin a, b, 1 , Yi-Hsien Fang a , Ling-Wei Hsu a , Sheng-Nan Wu c, d , Chia-Jui Yen a, e, f , Yen-Wen Liu a, f, g , Yu-Wei Hsiao h , Ju-Ming Wang d, h, i , Mohammad Saifur Rohman b , Ping-Yen Liu a, f, g, j, ⁎ Abstract |
Background |
Hepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models.
Objectives |
We sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity.
Methods |
We used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers.
Results |
Significantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis.
Conclusions |
TKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | PTX3 rose in sorafenib-treated patient plasma and cardiomyocyte culture medium. |
• | Anti-PTX3 antibody improved sorafenib-induced cardiotoxicity in cardiomyocytes. |
• | Anti-PTX3 antibody reversed sorafenib cardiotoxicity partly by the ERK-JNK pathway. |
• | TKI-induced sodium channel action potential disruption not reversed by anti-PTX3. |
• | Anti-PTX3 may serve as therapy for TKI-induced cardiotoxicity in cancer patients. |
Abbreviations : CEBPD, CPVT, CREB, CRP, DCM, ERK, HCC, hERG, hESCs, HF, IL-1β, iPSC, JNK, Kv4, LDL, LPS, LVSD, MAPK, MI, NaV, OCR, PDGFR, PTX3, PTX3i, RUES2-CM, SOR, TKI, TLR3, TNBC, TNFα, TSG6, VEGFR, VPC
Keywords : Cardiomyocytes, Hepatocellular carcinoma, Mitochondrial respiration, Pentraxin 3, Tyrosine kinase inhibitors, Cardiooncology
Plan
Vol 157
Article 113962- janvier 2023 Retour au numéro
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