P6305Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiomyopathy

Abstract

Background Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions, especially strongly upregulating interferon (IFN)-γ. Activation of iNKT cells have been previously reported to exert protective effects against post-infarcted cardiac remodeling and cardiac ischemia/reperfusion injury. However, the role of iNKT cells has not been determined in doxorubicin (DOX)-induced cardiomyopathy. Purpose The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (αGC), which specifically activates iNKT cells, could affect DOX-induced cardiomyopathy, and if so, to elucidate its downstream target. Methods C57BL/6J mice were received the intraperitoneal injection of either αGC (0.1μg/g, n=11) or vehicle (n=13). After 1 week, these mice were treated with a low dose of DOX (18mg/kg via intravenous 3 injections over 1 week), and were followed during 14 days. Results DOX mice (DOX+vehicle) showed left ventricular (LV) dysfunction and dilatation, which were significantly ameliorated in DOX mice receiving αGC (DOX+αGC) (LV fractional shortening: 27.4±4.31 vs. 31.5±4.62%, p<0.05, LV end-diastolic diameter: 3.70±0.16 vs. 3.32±0.23mm, p<0.05), with no significant changes in arterial pressure, body weight, and food consumption, 14 days after DOX injection. DOX+vehicle demonstrated a significant decrease in myocardial gene expression of Vα14Jα18, a specific marker of iNKT cells, and IFN-γ compared with control mice. Vα14Jα18 expression levels were higher in DOX+αGC than DOX+vehicle by 9.2 folds (p<0.05). Consistent with this change, IFN-γ was higher in DOX+αGC than DOX+vehicle by 4.4 folds (p<0.05), whereas interleukin (IL)-1, IL-4, IL-6, IL-10, IL-17, IL-23, and tumor necrosis factor (TNF)-α were not altered in both groups. Phosphorylation of Akt, its active form, in the heart was significantly increased in DOX+αGC compared with DOX+vehicle by 1.8 folds (p<0.05). Conclusions Activation of iNKT cells by αGC play a protective role against DOX-induced cardiac dysfunction, which was associated with enhancing expression of IFN-γ and activating Akt. Therapies designed to activate iNKT cells might be beneficial to protect the heart from DOX injury.

Bibliometric and visual analysis of doxorubicin-induced cardiotoxicity

“…Among the 20 highest-cited references, six articles explored the mechanisms of doxorubicin-induced acute cardiotoxicity (Chatterjee et al, 2010;Octavia et al, 2012;Sawaya et al, 2012;Zhang et al, 2012;Tacar et al, 2013;Cardinale et al, 2015), and the important keywords of oxidative stress, apoptosis, and expression were in red cluster. Oxidative stress and apoptosis play pivotal roles in cardiotoxicity, and several signaling pathways are implicated in mediating these processes (Paradies et al, 2018;Ikeda et al, 2019;Tian et al, 2020;Timm and Tyler, 2020;Wallace et al, 2020;Ahsan et al, 2021;Borisov et al, 2021;Li et al, 2021;FIGURE 5 The visualization of co-citation reference.…”

INKing the Cardiotoxicity Out of Doxorubicin

“…In a study reported in this issue of JACC: Basic to Translational Science , Sada et al 3 investigated the hypothesis that activation of iNKT cells by α-GC attenuates Dox-induced cardiomyocyte death and explored the underlying molecular mechanisms. To do this, the investigators used α-GC to activate iNKT cells, confirmed its cardioprotective role in Dox cardiotoxicity, and defined the downstream role of IFN-γ–signal transducers and activators of transcription 1 (STAT1)– extracellular signal-regulated kinase (ERK) pathway.…”

“…To do this, the investigators used α-GC to activate iNKT cells, confirmed its cardioprotective role in Dox cardiotoxicity, and defined the downstream role of IFN-γ–signal transducers and activators of transcription 1 (STAT1)– extracellular signal-regulated kinase (ERK) pathway. After validating α-GC as an activator of iNKT in Dox-treated hearts, Sada et al 3 found that α-GC prevents Dox-induced weight loss and cardiac dysfunction. Using echocardiography, the investigators found that administration of α-GC attenuated Dox-induced cardiac dysfunction, as well as attenuated cardiac atrophy.…”

“…In mechanistic studies, Sada et al 3 first evaluated the downstream targets of IFN-γ and found that α-GC administration increased total protein level and phosphorylation of STAT1, a direct downstream of IFN-γ receptor, in the presence or absence of Dox. Interestingly, among multiple STAT1 targets, α-GC increased phosphorylation of ERK and Akt, but not c-Jun N-terminal kinase or p38.…”

“…Mass spectrometry in control, Dox, and Dox plus α-GC hearts suggested that α-GC administration alters biomarkers related to energy metabolism and antioxidant capacity, which are intimately involved in cardiomyocyte death. To elucidate the role and importance of IFN-γ in protective effects of iNKT cells in Dox-induced cardiotoxicity, Sada et al 3 administrated neutralizing anti–IFN-γ monoclonal antibody into mice treated with Dox and α-GC. After a series of experiments, the investigators demonstrated that blockage of IFN-γ abolished the cardioprotective effects of iNKT cell activation by α-GC on Dox-induced cardiac dysfunction and apoptosis.…”