The novel butyrate derivative phenylalanine‐butyramide protects from doxorubicin‐induced cardiotoxicity

Abstract

AimsButyric 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.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 H 2 O 2 , 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.

Short-chain fatty acid, acylation and cardiovascular diseases

“…Treatment with butyrate attenuates fractional abdominal aorta ligation-stimulated myocardial hypertrophy, as confirmed by reduced collagen content and preservation of left ventricle systolic and diastolic dysfunction through reducing oxidative stress and increasing mitochondrial DNA concentration [119]. More interestingly, butyrate derivative phenylalanine-butyramide also protects against doxorubicin-stimulated cardiotoxicity through regulating oxidative stress and improving the function of mitochondria [120]. Therefore, butyrate serves as a cardioprotective factor partially via repressing oxidative stress.…”

TLR9 deficiency alleviates doxorubicin‐induced cardiotoxicity via the regulation of autophagy

“…Therefore, DOX inevitably brings a series of anti‐cancer side effects, of which cardiac toxicity is the most highlighted and lethal. Numerous studies have reported the important role of redox cycling and ROS generation in DOX‐induced cardiotoxicity 19,29 . However, intervention with an ROS inhibitor failed to rescue cardiotoxicity, 19 which thereby suggests the existence of additional factors.…”

Novel Basic Science Insights to Improve the Management of Heart Failure: Review of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology

“…SCFA bind several transmembrane receptors, mediating effects on blood pressure, glucose homeostasis, appetite, obesity [94]. In particular, butyrate has long been recognized important to maintain gut barrier function and to exert beneficial effects when administered exogenously in several experimental models of CVD [95,96]. Recently, propionate has also been shown to significantly attenuate cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in two different mouse models of hypertensive cardiovascular damage [97], even if its precise role in HF remains largely undetermined.…”