Abstract
The toxicity of doxorubicin to the cardiovascular system often limits its benefits and widespread use as chemotherapy. The mechanisms involved in doxorubicin-induced cardiovascular damage and possible protective interventions are not well-explored. Using human aortic endothelial cells, we show vitamin D3 strongly attenuates doxorubicin-induced senescence and cell cycle arrest. We further show the protective effects of vitamin D3 are mediated by the upregulation of IL-10 and FOXO3a expression through fine modulation of pAMPKα/SIRT1/FOXO3a complex activity. These results have great significance in finding a target for mitigating doxorubicin-induced cardiovascular toxicity.
Highlights
Doxorubicin (DOX) continues to be a frontline, broad-spectrum, anticancer agent
Using quantitative real-time PCR, we further examined the mRNA expression levels of Interleukin 10 (IL-10) in human aortic endothelial cells (HAECs) exposed to DOX
The primary findings of our study are as follows: 1. vitamin D3 (VitD3) protects against DOX-induced senescence of HAECs primarily via upregulation of IL-10 expression
Summary
Leading to heart failure, have limited the widespread use of DOX in cancer patients [1]. Any damage to the endothelium can multiply the cardiotoxic potential of DOX, leading to more severe cardiomyopathy. DOX-induced endothelial dysfunction can enhance vascular damage via known risk factors, such as the inflammatory milieu, hyperlipidemia, hypertension, and diabetes mellitus [6]. This can lead to a progressive decline in cardiomyocyte health and contribute to chronic cardiomyopathy. The potential of DOX to compromise vascular health has led to a recent paradigm shift, making the endothelium a novel upstream target for the prevention of DOX-induced cardiomyopathy
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