Key result
Sunitinib downregulates miR-146a, causing a 20% decrease in LVEF in mice, while AAV9-mediated miR-146a overexpression protects against this cardiac contractile dysfunction.
Why the study?
Cardiac contractile dysfunction is the main adverse effect of tyrosine kinase inhibitors like sunitinib, but the molecular mechanisms remain largely obscure.
Does miR-146a overexpression prevent sunitinib-induced cardiac contractile dysfunction in preclinical models?
Does miR-146a overexpression prevent sunitinib-induced cardiac contractile dysfunction in preclinical models?
Overexpression of miR-146a protects against sunitinib-induced cardiac contractile dysfunction by targeting PLN and ANK2 in preclinical models, identifying a potential therapeutic target for tyrosine kinase inhibitor-induced cardiotoxicity.
Answers are grounded in this paper and cite their sources.
Sunitinib cardiotoxicity may involve miR-146a loss in mice; leaves open whether miR-146a restoration prevents LVEF decline in patients.
The main adverse effect of tyrosine kinase inhibitors such as sunitinib is cardiac contractile dysfunction, but the molecular mechanisms remain largely obscure. MicroRNAs (miRNAs) are key regulatory factors in both cardiovascular diseases and the tyrosine kinase pathway. Therefore, we analyzed the differential expression of miRNAs in the myocardium after exposure to sunitinib in mice using miRNA microarray. A significant downregulation of miR-146a was observed in myocardium from sunitinib-treated mice, concomitantly with a 20% decrease in left ventricle ejection fraction (LVEF). The downregulation of miR-146a was further validated by RT-qPCR. Among the potential targets of miR-146a, we focused on Pln and Ank2, which are closely related to cardiac contractile dysfunction. A luciferase reporter assay confirmed that miR-146a directly targets the 3 'untranslated region of Pln and Ank2. Significant upregulation of PLN and ANK2 both at mRNA and protein levels was found in myocardium from sunitinib-treated mice. Cardiac-specific overexpression of miR-146a through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery protect against the decrease of LVEF in sunitinib-treated mice, along with evident recovery in the expression levels of both PLN and ANK2. Moreover, MiR-146a overexpression significantly alleviated the decreased contractility of human induced pluripotent stem cell-derived cardiomyocytes in vitro. Therefore, our results from in vivo and in vitro demonstrate that sunitinib downregulates miR-146a, which contributes to cardiac contractile dysfunction through downstream targets, PLN and ANK2; and upregulation of miR-146a alleviates the inhibition of SNT on cardiac contractility. Thus, miR-146a could be a useful agent for protection against sunitinib-induced cardiac dysfunction.
No takes yet. Share an insight, caveat, or question.
Shen et al. (2019) studied Sunitinib-induced cardiac dysfunction. Sunitinib and miR-146a overexpression was evaluated on Left ventricle ejection fraction (LVEF) and cardiac contractility. Sunitinib downregulates miR-146a, causing a 20% decrease in LVEF in mice, while AAV9-mediated miR-146a overexpression protects against this cardiac contractile dysfunction.
Synapse has enriched 10 related papers. Consider them for comparative context: