![]() ![]() ![]() The 2 major iron containing molecules in the body are Fe/S clusters and heme. Thus, the levels of iron are tightly regulated to provide sufficient amount of the molecule for important cellular processes while preventing iron‐mediated ROS production. However, this redox activity of iron can also lead to the production of hydroxyl radicals, the most toxic reactive oxygen species (ROS). Iron can quickly transform between a reduced ferrous (Fe 2+) and oxidative ferric (Fe 3+) state, 16 a property which is important for many catalytic processes. Iron is an essential metal that is necessary for normal cellular processes, including metabolism, heme synthesis, cell proliferation, cytochrome p450 enzyme activity, and hypoxic response. 15 Through modulation of ISCU, miR‐210 has been shown to alter mitochondrial respiratory complex activity and mitochondrial function. Furthermore, several reports have indicated that miR‐210 targets iron‐sulfur cluster scaffold proteins (ISCU 1/2), 11, 12, 13 an important protein for the synthesis of iron‐sulfur clusters 14 and consequently proper functioning of the electron transport chain. 10 Our group has also demonstrated that miR‐210 may have protective effects against oxidant‐induced cell death and reduce the production of reactive oxygen species in isolated cardiomyocytes. 9 In the heart, miR‐210 overexpression using minigenes in mice has been shown to improve cardiac function and reduce injury after myocardial infarction. miR‐210 has been shown to possess diverse functions, including modulation of angiogenesis, 7 stem cell survival, 8 and hypoxia‐induced cell cycle arrest. However, recent evidence has demonstrated its regulation by p53‐ and AKT‐dependent pathways, as well. It is regulated by hypoxia‐inducible factor (HIF). MiRNA‐210 (miR‐210) levels have been shown to increase in response to hypoxia in various cell types, including cardiac cells. 5 miRNAs have both beneficial and detrimental effects in cardiac physiology. These include cardiac development, 2 cardiac hypertrophy, 3 heart failure, 4 and angiogenesis. 1 The role of miRNAs in several cardiac physiological and pathological processes has been characterized. It is predicted that miRNAs target and regulate about 30% of the mammalian genome. Micro‐ribonucleic acids (miRNAs) are small 22 nucleotide RNA molecules that regulate gene expression by binding to the 3′ untranslated region (UTR) of messenger RNA (mRNA). Finally, FECH levels increased in hypoxia, and this effect was not reversed by miR‐210 knockdown, suggesting that the effects of miR‐210 on heme are restricted to normoxic conditions, and that the pathway is overriden in hypoxia. Changes mediated by miR‐210 in heme and FECH were independent of ISCU, as overexpression of an ISCU construct lacking the 3′ UTR does not alter miR‐210 regulation of heme and FECH. ![]() Mutation of the 2 miR‐210 binding sites in the 3′ untranslated region ( UTR) of FECH reversed the miR‐210 response, while mutation of either binding site in isolation did not exert any effects. Furthermore, miR‐210 reduced cellular heme levels and the activity of mitochondrial and cytosolic heme‐containing proteins by modulating ferrochelatase ( FECH), the last enzyme in heme biosynthesis. Levels of miR‐210 are significantly increased with iron chelation, however, this response was mediated entirely through the hypoxia‐inducible factor ( HIF) pathway. To screen for micro‐ribonucleic acids (miRNAs) regulated by iron, we performed a mi RNA gene array in neonatal rat cardiomyocytes treated with iron chelators. Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). ![]()
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |