Cardiac Troponins are Among Targets of Doxorubicin-Induced Cardiotoxicity in hiPCS-CMs

Abstract

Modern diagnostic strategies for early recognition of cancer therapeutics-related cardiac dysfunction involve cardiac troponins measurement. Still, the role of other markers of cardiotoxicity is still unclear. The present study was designed to investigate dynamics of response of human cardiomyocytes derived from induced pluripotent stem cells (hiPCS-CMs) to doxorubicin with the special emphasis on their morphological changes in relation to expression and organization of troponins. The hiPCS-CMs were treated with doxorubicin concentrations (1 and 0.3 µM) for 48 h and followed for next up to 6 days. Exposure of hiPCS-CMs to 1 µM doxorubicininduced suppression of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) gene expression. Conversely, lower 0.3 µM doxorubicin concentration produced no significant changes in the expression of aforementioned genes. However, the intracellular topography, arrangement, and abundance of cardiac troponin proteins markedly changed after both doxorubicin concentrations. In particular, at 48 h of treatment, both cTnT and cTnI bundles started to reorganize, with some of them forming compacted shapes extending outwards and protruding outside the cells. At later intervals (72 h and onwards), the whole troponin network collapsed and became highly disorganized following, to some degree, overall changes in the cellular shape. Moreover, membrane permeability of cardiomyocytes was increased, and intracellular mitochondrial network rearranged and hypofunctional. Together, our results demonstrate complex effects of clinically relevant doxorubicin concentrations on hiPCS-CM cells including changes in cTnT and cTnI, but also in other cellular compartments contributing to the overall cytotoxicity of this class of cytostatics.

Intracellular action potential recordings from cardiomyocytes by ultrafast pulsed laser irradiation of fuzzy graphene microelectrodes

“…On hiPSC-CMs, the results demonstrated a substantial expression of cardiac troponin T (green) that highlights a myocardial structure, as expected for mature hiPSC cardiomyocytes ( Fig. 2A ) ( 30 ). The images also show a substantially low expression of NKX2-5 (red), a marker of cardiac progenitor cells, with only 15.38 ± 3.47% of the cells expressing NKX2-5.…”

Irvingia gabonensis Seed Extract: An Effective Attenuator of Doxorubicin-Mediated Cardiotoxicity in Wistar Rats

“…DOX administration may result in the damage to the myocardial cell membrane or make myocytes more permeable, resulting in the leakage of the diagnostic cardiac enzyme markers cardiac AST, ALT, CK-MB, LDH, and cTnI into the bloodstream and their high circulating levels. In the present study, DOX-mediated cardiotoxicity was fully established as evidenced by the profound elevations in the serum cTnI and LDH levels which is in complete agreement with previous studies [ 47 – 52 ]. With oral IGESE pretreatments, the serum levels of cTnI and LDH were profoundly attenuated toward normal serum level indicating the ameliorative potential of IGESE in DOX-mediated cardiotoxicity.…”

Cannabinoid Receptors in Myocardial Injury: A Brother Born to Rival

“…However, anthracyclines such as doxorubicin (DOX) are still important in first-line treatment for breast cancer, lymphoma, sarcoma, and childhood hematological malignancy, owing to a lack of effective alternatives [74]. The subclinical damage caused by the cardiotoxic effect of anthracyclines, especially doxorubicin (DOX), is most frequently observed [75][76][77].…”