XO can transfer electrons to molecular oxygen, resulting in the formation of superoxide during xanthine or hypoxanthine oxidation and promoting further heart damage. For example, xanthine oxidase (XO), which represents an oxidized form of xanthine dehydrogenase (XDH), forms in damaged tissues, including rat hearts with myocardial ischemia. The main intracellular sources of ROS are the electron transport chain (ETC) of mitochondria (see below) and certain enzymes that generate ROS as reaction by-products. The main intracellular origin of ROS is the mitochondria, but other cellular sites, such as the endoplasmic reticulum (ER), peroxisomes, and actin cytoskeleton, lysosome, plasma membrane, and cytosol are also known to supply ROS (reviewed in ). Exogenous sources include exposure to radiation or high levels of transition metals, heavy metals, and several anticancer drugs.
ROS can be supplied from the environment or from within the cell. – and promotes protein and lipid oxidation.Īmong non-enzymatic antioxidants is the highly abundant, short (three amino acid) peptide glutathione (GSH), the intracellular concentration of which ranges between 1–10mM depending on the cell type vitamins C and E.Under pathological conditions, such as atherosclerosis and hypertension or upon mutation-mediated conformational rearrangements, Sod1 gains an ability to interact with H 2O 2 instead of O 2 The best studied example is superoxide dismutase 1 (Sod1), also known as Cu/Zn dismutase. However, some of these defense enzymes exhibit pro-oxidant properties in pathological states. Upon detecting this ROS molecule, Yap1 and NRF2 translocate to the nucleus to promote synthesis of antioxidant defense enzymes, such as catalases, superoxide dismutases, thioredoxin-dependent peroxiredoxins, and glutathione peroxidases, all of which have their own substrate preferences and mechanisms of catalysis. For example, transcription factors Yap1 from yeast and NRF2 from mammalian cells are capable of sensing low-dose H 2O 2. Signaling properties of ROS include activation of cellular kinases, inhibition of phosphatases, and upregulation of activities of certain transcriptional factors (reviewed in ). At the same time, ROS may play a cytoprotective role by attacking invading pathogens or acting as signaling molecules. ROS can target, terminally modify, and damage any biomolecule in a cell, such as lipids, proteins, and nucleic acids. The goal of this review is to summarize our current knowledge of molecular alterations that occur within the translational machinery in response to reactive oxygen species (ROS) and lead to various cardiovascular pathologies. Many excellent reviews summarize the effects of translational errors and disturbed proteostasis on the development of neurodegenerative disorders, while cardiovascular diseases (CVDs), the leading cause of death worldwide ( ), have received less attention. Therefore, it is not surprising that any abnormalities in protein translation, caused by internal or external insults, that result in production of anomalous and potentially deleterious proteins, manifest in the development and progression of a plethora of human diseases. To efficiently produce a faultless cellular proteome in a cell, protein translation is tightly controlled, aiming to establish protein homeostasis (proteostasis) to maintain healthy cellular physiology. This complex process employs multiple essential players, including ribosomes, mRNAs, tRNAs, and numerous translational factors, enzymes, and regulatory proteins. The process of protein synthesis, or protein translation, constitutes the last and final step of the central dogma of molecular biology: assembly of polypeptides based on the information encoded by mRNAs.