Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Abstract

Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

Irisin ameliorates doxorubicin-induced cardiac perivascular fibrosis through inhibiting endothelial-to-mesenchymal transition by regulating ROS accumulation and autophagy disorder in endothelial cells

“…A recent study showed that the classic TGF-β/smads pathway was involved in DOX-induced EndMT of CMECs [ 34 ], which is inconsistent with our results. In their in vitro experiments, the phenotype of EndMT was not induced by DOX stimulation, but directly by TGF-β treatment, which was not rigorous.…”

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

“…Calcitriol, an active form of vitamin D3 that inhibits the growth of cancer cells, has been shown to attenuate Doxinduced myocardial fibrosis and fibrotic proteins, and improve diastolic function by reducing TGF-β-Smad2mediated EndMT and fibroblast-to-myofibroblast transition. The hearts of mice with EC-specific GFP expression showed increased levels of vimentin + GFP + ECs (indicative of EndMT), whereas calcitriol treatment attenuated these effects 79 . Administration of arsenic trioxide induced cardiac fibrosis in rats.…”

Kanglexin protects against cardiac fibrosis and dysfunction in mice by TGF-β1/ERK1/2 noncanonical pathway

“…A landmark study published in 2007 confirmed that EndMT is involved in cardiac fibrosis of the adult heart ( Zeisberg et al, 2007 ). Many studies demonstrated that the inhibition of EndMT might be a useful strategy in the therapy of cardiac fibrosis ( Song et al, 2019 ; Tsai et al, 2019 ). In this study, we demonstrated the potential regulation of KLX on EndMT in TAC mice.…”