Michele Russo1,2, Fiorentina Guida1, Lorella Paparo1, Giovanna Trinchese3, Rosita Aitoro1, Carmen Avagliano4, Antonella Fiordelisi5, Fabiana Napolitano6, Valentina Mercurio1, Valentina Sala2, Mingchuan Li2, Daniela Sorriento5, Michele Ciccarelli7, Alessandra Ghigo2, Emilio Hirsch2, Roberto Bianco6,8, Guido Iaccarino5, Pasquale Abete1, Domenico Bonaduce1,9, Antonio Calignano4, Roberto Berni Canani1,9,10,11, Carlo G Tocchetti1,8,9. 1. Department of Translational Medical Sciences, 'Federico II' University, Naples, Italy. 2. Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Turin, Italy. 3. Department of Biology, 'Federico II' University, Naples, Italy. 4. Department of Pharmacy, 'Federico II' University, Naples, Italy. 5. Department of Advanced Biomedical Sciences, 'Federico II' University, Naples, Italy. 6. Department of Clinical Medicine and Surgery, 'Federico II' University, Naples, Italy. 7. Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy. 8. Interdipartimental Center for Clinical and Translational Research (CIRCET), 'Federico II' University, Naples, Italy. 9. Task Force for the Microbiome Studies, 'Federico II' University, Naples, Italy. 10. CEINGE Advanced Biotechnologies, 'Federico II' University, Naples, Italy. 11. European Laboratory for the Investigation of Food Induced Diseases (ELFID), 'Federico II' University, Naples, Italy.
Abstract
AIMS: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. METHODS AND RESULTS: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2 O2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. CONCLUSIONS: Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
AIMS: Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. METHODS AND RESULTS: In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXOmice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2 O2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. CONCLUSIONS:Phenylalanine-butyramide protects against experimental doxorubicincardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.
Authors: Brandon Y H Chan; Andrej Roczkowsky; Woo Jung Cho; Mathieu Poirier; Consolato Sergi; Vic Keschrumrus; Jared M Churko; Henk Granzier; Richard Schulz Journal: Cardiovasc Res Date: 2021-01-01 Impact factor: 10.787
Authors: Marco Bruno Morelli; Chiara Bongiovanni; Silvia Da Pra; Carmen Miano; Francesca Sacchi; Mattia Lauriola; Gabriele D'Uva Journal: Front Cardiovasc Med Date: 2022-04-15