Abstract
The main adverse effect of tyrosine kinase inhibitors, such as sunitinib, is cardiac contractile dysfunction; however, the molecular mechanisms of this effect 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 in mice after exposure to sunitinib using miRNA microarray. A significant downregulation of miR-146a was observed in the myocardium of sunitinib-treated mice, along 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. Results of luciferase reporter assay confirmed that miR-146a directly targeted the 3′ untranslated region of Pln and Ank2. Significant upregulation of PLN and ANK2 at the mRNA and protein levels was observed in the myocardium of sunitinib-treated mice. Cardiac-specific overexpression of miR-146a prevented the deteriorate effect of SNT on calcium transients, thereby alleviating the decreased contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). SiRNA knockdown of PLN or ANK2 prevented sunitinib-induced suppression of contractility in hiPSC-CMs. Therefore, our in vivo and in vitro results showed that sunitinib downregulated miR-146a, which contributes to cardiac contractile dysfunction by regulating the downstream targets PLN and ANK2, and that upregulation of miR-146a alleviated the inhibitory effect of SNT on cardiac contractility. Thus, miR-146a could be a useful protective agent against sunitinib-induced cardiac dysfunction.
Highlights
Small molecule inhibitors targeting receptor tyrosine kinases have markedly improved the life expectancy of cancer patients (Motzer et al, 2006)
Recent studies have shown that decreased intracellular Ca2+ transition contributes to SNT-induced negative inotropic effect (Rainer et al, 2012), which may result from its effect on phospholamban (PLN), a key regulator of sarcoplasmic endoreticulum Ca2+-ATPase (SERCA) (Schneider et al, 2018)
Rainer et al (2012) have performed a comprehensive analysis of alterations in the expression of microRNAs in cultured HL-1 cells, a murine cardiomyocytic cell line; they did not find any differential expression of microRNA after exposure of cells to SNT for 24 h (Rainer et al, 2012)
Summary
Small molecule inhibitors targeting receptor tyrosine kinases have markedly improved the life expectancy of cancer patients (Motzer et al, 2006). Many of these agents have unintended consequences on the cardiovascular system, including hypertension, left ventricular (LV) dysfunction, and chronic heart failure (Richards et al, 2011). MiR-146a Contributes to Sunitinib-Induced Cardiac Dysfunction (LVEF), and 8–15% of patients develop congestive heart failure (CHF) (Chu et al, 2007). A specific protective drug or approach to prevent the side effects of SNT is still not available because information on the molecular mechanisms of cardiac contractile dysfunction remains limited (Faivre et al, 2007; Chen et al, 2008). The detailed molecular mechanism underlying the functional effect of SNT on PLN is unknown
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