ABSTRACT
BACKGROUND AND PURPOSE: 5-fluorouracil (5FU) and its prodrug, capecitabine, can damage endothelial cells, whilst endothelial integrity is preserved by glucagon-like peptide 1 (GLP-1). Here, we studied the effect of 5FU on endothelial senescence and whether GLP-1 antagonizes it. EXPERIMENTAL APPROACH: EA.hy926 cells were exposed to 5FU or sera from patients taking capecitabine, with or without pre-incubation with GLP-1. Senescence was identified by expression of senescence-associated ß-galactosidase and p16INK4a and reduced cell proliferation. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and CD146 (marker of endothelial injury) were measured by ELISA before and at completion of capecitabine chemotherapy. RT-PCR, western blotting, functional experiments with signalling inhibitors and ERK1/2 silencing were performed to characterize 5FU-induced phenotype and elucidate the pathways underlying 5FU and GLP-1 activity. KEY RESULTS: Both 5FU and sera from capecitabine-treated patients stimulated endothelial cell senescence. 5FU-elicited senescence occurred via activation of p38 and JNK, and was associated with decreased eNOS and SIRT-1 levels. Furthermore, 5FU up-regulated VCAM1 and TYMP (encodes enzyme activating capecitabine and 5FU), and sVCAM-1 and CD146 concentrations were higher after than before capecitabine chemotherapy. A non-significant trend for higher ICAM1 levels was also observed. GLP-1 counteracted 5FU-initiated senescence and reduced eNOS and SIRT-1 expression, this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K. CONCLUSIONS AND IMPLICATIONS: 5FU causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects. 5FU-triggered senescence was prevented by GLP-1, raising the possibility of using GLP-1 analogues and degradation inhibitors to treat 5FU and capecitabine vascular toxicity. LINKED ARTICLES: This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc.
Subject(s)
Capecitabine/administration & dosage , Cellular Senescence/drug effects , Endothelial Cells/drug effects , Fluorouracil/toxicity , Glucagon-Like Peptide 1/administration & dosage , Aged , Antimetabolites, Antineoplastic/toxicity , Blotting, Western , Cell Line , Endothelial Cells/pathology , Enzyme-Linked Immunosorbent Assay , Female , Glucagon-Like Peptide 1/pharmacology , Humans , Male , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Patients with submassive pulmonary embolism (PE), although normotensive, are characterized by right ventricular (RV) dysfunction and elevated levels of biomarkers of cardiac damage. The best treatment option in these cases is still a subject of debate and the use of thrombolysis in submassive PE remains controversial. A 57-year-old Caucasian male with unprovoked PE, normal blood pressure, and elevated troponin I values was referred to the cardiovascular department. In view of the presence of a right atrium thrombus, the patient underwent surgical embolectomy under extracorporeal circulation, with the extraction of a huge thrombus together with fragmented thrombi from both pulmonary arteries. The patient developed an acute right heart failure solved with a temporary RV assist device (RVAD) support. The RV recovery was observed after 72 hours following the implantation. RVAD placement should be considered in the management of PE in case of acute right heart failure after reperfusion therapy since it can bring the patient out of a death spiral.
