Transient Exposure of Endothelial Cells to Doxorubicin Leads to Long-Lasting Vascular Endothelial Growth Factor Receptor 2 Downregulation

Abstract

Doxorubicin (Dox) is an effective antineoplastic drug with serious cardiotoxic side effects that persist after drug withdrawal and can lead to heart failure. Dysregulation of vascular endothelium has been linked to the development of Dox-induced cardiotoxicity, but it is unclear whether and how transient exposure to Dox leads to long-term downregulation of Endothelial Vascular Endothelial Growth Factor Receptor type2 (VEGFR2), essential for endothelial cells function. Using an in vitro model devised to study the long-lasting effects of brief endothelial cells exposure to Dox, we show that Dox leads to sustained protein synthesis inhibition and VEGFR2 downregulation. Transient Dox treatment led to the development of long-term senescence associated with a reduction in VEGFR2 levels that persisted days after drug withdrawal. By analyzing VEGFR2 turnover, we ruled out that its downregulation was depended on Dox-induced autophagy. Conversely, Dox induced p53 expression, reduced mTOR-dependent translation, and inhibited global protein synthesis. Our data contribute to a mechanistic basis to the permanent damage caused to endothelial cells by short-term Dox treatment.

EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263

“…We found that DOX induced the senescence markers p53 and p21 in HUVECs, in agreement with previous studies [31,32]. This was also consistent with another study of DOX-induced senescence in human aortic endothelial cells, another type of primary ECs [12].…”

Role of non-cardiomyocytes in anticancer drug-induced cardiotoxicity: A systematic review

“…VEGFR2 is a highly expressed tyrosine kinase receptor in endothelial cells, and its related signaling determines whether heart growth is physiological or pathological ( Liu et al., 2020 ). In order to study the short-term effects of Dox, a model was established that endothelial cells are briefly exposed to low concentrations of Dox and analyzed a few days after drug clearance ( Graziani et al., 2022 ). Studies have shown that Dox leads to the aging of Endothelial cells and continuously inhibits the expression level of VEGFR2.…”

“…VEGFR2 levels were halved within 6 h of Dox treatment, in that autophagy can degrade proteins in a short period according to previous research experience, though it was not a decisive factor. Reversely, Dox decreases VEGFR2 levels by inhibiting mTOR and persists after sloping administration ( Graziani et al., 2022 ).…”

The Impairment of Cell Metabolism by Cardiovascular Toxicity of Doxorubicin Is Reversed by Bergamot Polyphenolic Fraction Treatment in Endothelial Cells

“…In particular, the accumulation of DOX in the mitochondria determines the uncoupling of OXPHOS complexes, with a consequent reduction in adenosine triphosphate (ATP) synthesis and a simultaneous increase in the AMP/ATP ratio, resulting in the activation of AMP-activated protein kinase. DOX-induced mitochondrial dysfunction also alters the intracellular calcium balance [ 14 , 15 ]. DOX has been shown to reduce mitochondrial membrane potential, open mitochondrial permeability transition pore (mPTP), and activate the ROS-induced ROS release mechanism, resulting in mitochondrial dysfunction, causing damage to the vascular endothelium (VE) [ 16 ].…”

“…DOX has been shown to reduce mitochondrial membrane potential, open mitochondrial permeability transition pore (mPTP), and activate the ROS-induced ROS release mechanism, resulting in mitochondrial dysfunction, causing damage to the vascular endothelium (VE) [ 16 ]. In fact, DOX also damages non-cardiomyocyte heart cells such as endothelial cells (ECs) [ 5 , 11 , 14 ]. DOX can enter ECs through SLC22A1 and interfere, for example, with endothelial nitric oxide synthase (eNOS), which is the NOS isoform most sensitive to DOX [ 12 , 17 ].…”