Hypoxia is a critical environmental stressor to which cardiomybcytesare subjected during myocardial ischemia. MicroRNAs are a class of small RNA molecules which inhibit translation of protein-encoding messenger RNAs. They play critical roles in cardiac development and function. Yet the role of microRNAsin the hypoxia response of cardiomyocytes remains unknown. MicroRNA-210 (miR-210) is profoundly upregulated when neonatal rat cardiomyocytes (NRCMs) are exposed to hypoxia. We hypothesize that this upregulation of miR-210 is cytoprotective against oxidative stress in cardiomyocytes. We further hypothesize that putative targets of miR-210 include hypoxia-inducible factor 3-alpha (HIF-3a), a negative regulator of HIF-1a, and iron-sulfur cluster scaffold homolog (IscU), a very highly conserved protein involved in iron-sulfur protein synthesis. Iron-sulfur proteins constitute an integral part of the electron transport chain and oxidative phosphorylation. These putative targets may play fundamental roles in hypoxia signaling. We will test these hypotheses by pursuing 3 specific aims: 1. To determine whether miR-210 overexpression reduces oxidant-induced cell death. 2. To determine whether miR-210 knockdown reduces survival in the presence of hypoxia. 3. To identify and validate putative targets of miR-210 with potential roles in hypoxia signaling, including HIF-3a and IscU. The major goal of this project is to elucidate the role of miR-210 in cardiomyocyte survival during oxidative stress. The long-term objective of this research is to identify novel therapeutic targets for cytoprotection during myocardial ischemia. This project is highly relevant to public health. Myocardial infarction, the death of heart tissue because of a sudden cessation of blood flow to the heart, is one of the top causes of death and disability in the United States. Cell death does not happen immediately, however, and protecting cells from dying until blood flow is restored may therefore be a useful strategy. In this project, we explore the role that a new molecule, microRNA-210, may play in protecting heart cells from death as well as possible mechanisms for this effect.
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