Biology subjects

Vaparanta, K. M.

Publications and source records attributed to Vaparanta, K. M..

3 recordsLinked to original sources

bioRxiv2024

Heat stress sensitizes zebrafish embryos to neurological and cardiac toxicity.

Global warming increases the risk of dangerous heat waves, which may have deleterious effects on humans and wildlife. Here, we have utilized zebrafish embryos as a model to analyse heat stress and effect of chemical compounds on responses to heat stress. The temperature adaptation limit of zebrafish embryos was 37{degrees}C in behavioural test and 38{degrees}C in cardiac test. Polyaromatic hydrocarbon phenanthrene completely blocked the behavioural adaptation to heat stress. Interestingly, the cardiotoxic effects of lapatinib, phenanthrene and paclitaxel were induced by heat stress. Taken together, our data indicates that motility and cardiac function of zebrafish embryos can be utilized as a model to analyze modulatory effects of compounds on heat stress. HighlightsO_LIZebrafish embryos can be utilized as an in vivo model for acute heat stress C_LIO_LIPhenanthrene inhibited motility increase upon heat stress C_LIO_LICardiotoxicity of lapatinib, paclitaxel and phenanthrene was potentiated by heat stress C_LI

pharmacology and toxicology↗

bioRxiv2024

Phosphoproteomic analysis reveals the diversity of signaling behind ErbB inhibitor-induced phenotypes

The impact of kinase inhibitors on the phosphoproteome has been rarely investigated at a whole organism level. Here we performed a phosphoproteomic analysis in embryonic zebrafish to identify the signaling pathways perturbed by ErbB receptor tyrosine kinase inhibitors at the organism level. The phosphorylation of proteins associated with the PI3K/Akt, p38 MAPK, Notch, Hippo/Yap and {beta}-catenin signaling pathways were differentially regulated by the ErbB inhibitors. Gene set enrichment analyses indicated differential neurological and myocardial phenotypes of different ErbB inhibitors. To assess the neurological and myocardial effects, motility and ventricle growth assays were performed on zebrafish embryos treated with the ErbB and downstream signaling pathway inhibitors. The treatment with the inhibitors targeting the PI3K/Akt, p38 MAPK, and Notch signaling pathways along with the ErbB inhibitors AG1478 and Lapatinib perturbed the overall movement and ventricle wall growth of zebrafish embryos. Taken together, these results indicate that inhibitors with the same primary targets can affect different signaling pathways while eliciting similar physiological phenotypes.

cell biology↗

bioRxiv2022

STAT5b is a key effector of NRG-1/ERBB4-mediated cardiomyocyte growth

The growth factor neuregulin-1 (NRG-1) regulates hypertrophic and hyperplastic myocardial growth and is currently under clinical investigation as a treatment for heart failure. We have previously demonstrated that an isoform of the NRG-1 receptor ERBB4 (ERBB4 JM-b) expressed in cardiomyocytes selectively regulates the activation of STAT5b. To explore the role of STAT5b in NRG-1/EBBB4 mediated cardiomyocyte growth, several in vitro and in vivo models were utilized. The downregulation of NRG-1/ERBB4 signaling consistently reduced STAT5b activation and transcription of STAT5b target genes Igf1, Myc and Cdkn1a in murine in vitro and in vivo models of myocardial growth. Stat5b knock-down in primary cardiomyocytes ablated NRG-1-induced cardiomyocyte hypertrophy. Stat5b was activated during NRG-1-induced hyperplastic myocardial growth and chemical inhibition of the Nrg-1/Erbb4 pathway led to the loss of myocardial growth and Stat5 activation in zebrafish embryos. Moreover, CRISPR/Cas9-mediated knock-down of stat5b in zebrafish embryos resulted in reduced myocardial growth and heart failure as indicated by reduced ventricular ejection fraction. Dynamin-2 was discovered to control the cell surface localization of ERBB4 and the chemical inhibition of dynamin-2 downregulated NRG-1/ERBB4/STAT5b signaling in models of hypertrophic and hyperplastic myocardial growth. Finally, the activation of the NRG-1/ERBB4/STAT5b signaling pathway was explored in clinical samples representing pathological cardiac hypertrophy. The NRG-1/ERBB4/STAT5b signaling pathway was differentially regulated both at the mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to myocardium of control subjects. These results establish the role for STAT5b, and dynamin-2 in NRG-1/ERBB4-mediated myocardial growth.

cell biology↗