4-hydroxy-2-nonenal and Cardiotoxicity

Topics: Aldehydes; Animals; Apoptosis; Cardiotoxicity; Caspase 3; Cell Line; Doxorubicin; Heme Oxygenase-1; Inflammation; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; NF-E2-Related Factor 2; Orosomucoid; Oxidative Stress; Rats; Signal Transduction

Doxorubicin (DOX) is a highly potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. DOX-induced cardiotoxicity involves increased oxidative stress and activated endoplasmic reticulum-mediated apoptosis. Alginate oligosaccharide (AOS) is a non-immunogenic, non-toxic and biodegradable polymer, with anti-oxidative, anti-inflammatory and anti-endoplasmic reticulum stress properties. The present study examined whether AOS pretreatment could protect against acute DOX cardiotoxicity, and the underlying mechanisms focused on oxidative stress and endoplasmic reticulum-mediated apoptosis. We found that AOS pretreatment markedly increased the survival rate of mice insulted with DOX, improved DOX-induced cardiac dysfunction and attenuated DOX-induced myocardial apoptosis. AOS pretreatment mitigated DOX-induced cardiac oxidative stress, as shown by the decreased expressions of gp91 (phox) and 4-hydroxynonenal (4-HNE). Moreover, AOS pretreatment significantly decreased the expression of Caspase-12, C/EBP homologous protein (CHOP) (markers for endoplasmic reticulum-mediated apoptosis) and Bax (a downstream molecule of CHOP), while up-regulating the expression of anti-apoptotic protein Bcl-2. Taken together, these findings identify AOS as a potent compound that prevents acute DOX cardiotoxicity, at least in part, by suppression of oxidative stress and endoplasmic reticulum-mediated apoptosis.

Topics: Aldehydes; Alginates; Animals; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Cardiotoxicity; Caspase 12; Chromatography, High Pressure Liquid; Doxorubicin; Endoplasmic Reticulum; Glucuronic Acid; Hexuronic Acids; Mice; Oligosaccharides; Oxidative Stress; Receptors, Immunologic; Spectrometry, Mass, Electrospray Ionization; Transcription Factor CHOP

Lipid peroxidation (LP), induced by oxidative stress, is associated with degenerative processes. 4-Hydroxy-2-nonenal (HNE), a highly reactive diffusible product of LP, is considered by-product and mediator of oxidative stress. Its level increases under pathological conditions such as cardiovascular diseases. In this study, we partially characterized the mechanisms of HNE-mediated cytotoxicity in cardiomyocytes. After establishing that pathophysiological doses of HNE trigger cell death dependent on the incubation time and dose of HNE (LD50 = 4.4 μM), we tackled the mechanisms that underlie the cell death induced by HNE. Our results indicate that HNE rapidly increases intracellular Ca(2+); it also increases the rate of reactive oxygen species generation and causes a loss of mitochondrial membrane potential (ΔΨm) as well as a decrease in the ATP and GSH levels. Such alterations result in the activation of caspase-3 and DNA breakdown, both characteristic features of apoptotic cell death, as well as disruption of the cytoskeleton. Moreover, the nucleophilic compounds N-acetyl-cysteine and β-mercapto-propionyl-glycine, and the synthetic antioxidant Trolox exert a potent antioxidant action against HNE damage; this suggests its use as effective compounds in order to reduce the damage occurred as consequence of cardiovascular disorders in which oxidative stress and hence LP take place.

Topics: Acetylcysteine; Aldehydes; Animals; Animals, Newborn; Antioxidants; Apoptosis; Calcium; Cardiotoxicity; Cells, Cultured; Chromans; Cysteine Proteinase Inhibitors; Cytoskeleton; Flow Cytometry; Lipid Peroxidation; Membrane Potential, Mitochondrial; Myocytes, Cardiac; Oxidative Stress; Rats; Rats, Wistar