Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin

• Published in: Scientific reports Vol. 10; no. 1; p. 14693
• Main Authors: Muhammad, Radwa Nasser, Sallam, Nada, El-Abhar, Hanan Salah
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.09.2020; Nature Publishing Group
• Subjects: 5-Fluorouracil; 631/337; 692/4019; 692/4028; 692/53; AKT protein; Animals; Antimetabolites, Antineoplastic - adverse effects; Aorta; Brain natriuretic peptide; Cardiomyocytes; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cardiotoxicity; Cardiotoxicity - drug therapy; Cardiotoxicity - metabolism; Cardiotoxicity - pathology; Caspase-3; Coronary artery; Cyclooxygenase-2; Endothelial cells; Endothelin 1; Endothelin-1 - metabolism; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Fluorouracil - adverse effects; Glutathione; Heart; Humanities and Social Sciences; Male; MAP Kinase Signaling System - drug effects; multidisciplinary; NAD(P)H oxidase; NF-κB protein; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Proto-Oncogene Proteins c-akt - metabolism; Rats, Wistar; Rho-associated kinase; rho-Associated Kinases - metabolism; Science; Science (multidisciplinary); Sensors; Signal Transduction - drug effects; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Solid tumors; Vasoconstriction; Vasodilation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-71531-8

5-Fluorouracil (5-FU) is used in the treatment of different solid tumors; however, its use is associated with rare, but serious cardiotoxicity. Nevertheless, the involvement of ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 trajectories in the cardiotoxic effect and in the potential cardioprotective upshot of simvastatin has been elusive. Male Wistar rats were allocated into 5-FU (50 mg/kg/week; i.p, 6 weeks), simvastatin (15 mg/kg/day; p.o, 8 weeks) treated groups and simvastatin + 5-FU, besides the normal control group. 5-FU-induced cardiotoxicity boosted the serum level of N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP), aortic contents of endothelin (ET)-1 and thromboxane (TX) A2, as well as cardiac contents of NADPH oxidases (Nox), cyclooxygenase (COX)-2, malondialdehyde (MDA), phosphorylated Akt ( p -Akt), phosphorylated extracellular signal-regulated kinase ( p -ERK)1/2 and the protein expressions of rho-kinase (ROCK) and caspase-3. On the other hand, it suppressed cardiac reduced glutathione (GSH) and phosphorylated endothelial nitric oxide synthase ( p -eNOS). Contrariwise, co-administration with simvastatin overcame these disturbed events and modulated the ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 signaling pathways. This study highlights other mechanisms than coronary artery spasm in the 5-FU cardiotoxicity and reveals that NT-proBNP is a potential early marker in this case. Moreover, the cross-talk between ROCK/ NF-κB, ROS/COX-2/TXA2, Akt/eNOS and ET-1/ERK1/2 pathways contributes via different means to upsetting the vasoconstriction/vasodilatation equilibrium as well as endothelial cell function and finally leads to cardiomyocyte stress and death—the modulation of these trajectories offers simvastatin its potential cardio-protection against 5-FU.