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The TGF-? pathway mediates doxorubicin effects on cardiac endothelial cells.

ABSTRACT: Elevated ALK4/5 ligands including TGF-? and activins have been linked to cardiovascular remodeling and heart failure. Doxorubicin (Dox) is commonly used as a model of cardiomyopathy, a condition that often precedes cardiovascular remodeling and heart failure. In 7-8-week-old C57Bl/6 male mice treated with Dox we found decreased capillary density, increased levels of ALK4/5 ligand and Smad2/3 transcripts, and increased expression of Smad2/3 transcriptional targets. Human cardiac microvascular endothelial cells (HCMVEC) treated with Dox also showed increased levels of ALK4/5 ligands, Smad2/3 transcriptional targets, a decrease in proliferation and suppression of vascular network formation in a HCMVEC and human cardiac fibroblasts co-culture assay. Our hypothesis is that the deleterious effects of Dox on endothelial cells are mediated in part by the activation of the TGF-? pathway. We used the inhibitor of ALK4/5 kinases SB431542 (SB) in concert with Dox to ascertain the role of TGF-? pathway activation in doxorubicin induced endothelial cell defects. SB prevented the suppression of HCMVEC proliferation in the presence of TGF-?2 and activin A, and alleviated the inhibition of HCMVEC proliferation by Dox. SB also prevented the suppression of vascular network formation in co-cultures of HCMVEC and human cardiac fibroblasts treated with Dox. Our results show that the inhibition of the TGF-? pathway alleviates the detrimental effects of Dox on endothelial cells in vitro.

SUBMITTER: Sun Z

PROVIDER: S-EPMC4718883 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells.

Sun Zuyue Z Schriewer Jill J Tang Mingxin M Marlin Jerry J Taylor Frederick F Shohet Ralph V RV Konorev Eugene A EA

Journal of molecular and cellular cardiology 20151211

Elevated ALK4/5 ligands including TGF-β and activins have been linked to cardiovascular remodeling and heart failure. Doxorubicin (Dox) is commonly used as a model of cardiomyopathy, a condition that often precedes cardiovascular remodeling and heart failure. In 7-8-week-old C57Bl/6 male mice treated with Dox we found decreased capillary density, increased levels of ALK4/5 ligand and Smad2/3 transcripts, and increased expression of Smad2/3 transcriptional targets. Human cardiac microvascular end ...[more]

PMID: 26686989

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Project description:The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.

Dataset Information

The TGF-? pathway mediates doxorubicin effects on cardiac endothelial cells.

Publications

The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells.

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