Abstract
Ischemia and subsequent reperfusion (IR) produces injury to brain, eye and other tissues, contributing to the progression of important clinical pathologies. The response of cells to IR involves activation of several signaling pathways including those activating hypoxia and heat shock responsive transcription factors. However, specific roles of these responses in limiting cell damage and preventing cell death after IR have not been fully elucidated. Here, we have examined the role of heat shock factor 1 (HSF1) in the response of zebrafish embryos to hypoxia and subsequent return to normoxic conditions (HR) as a model for IR. Heat shock preconditioning elevated heat shock protein expression and protected zebrafish embryo eye and brain tissues against HR-induced apoptosis. These effects were inhibited by translational suppression of HSF1 expression. Reduced expression of HSF1 also increased cell death in brain and eye tissues of embryos subjected to hypoxia and reperfusion without prior heat shock. Surprisingly, reduced expression of HSF1 had only a modest effect on hypoxia-induced expression of Hsp70 and no effect on hypoxia-induced expression of Hsp27. These results establish the zebrafish embryo as a model for the study of ischemic injury in the brain and eye and reveal a critical role for HSF1 in the response of these tissues to HR. Our results also uncouple the role of HSF1 expression from that of Hsp27, a well characterized heat shock protein considered essential for cell survival after hypoxia. Alternative roles for HSF1 are considered.
Highlights
A low tissue oxygen concentration, followed by the reintroduction of oxygen, gives rise to a phenomenon known as ischemia/ reperfusion injury, and is central to the progression of numerous human pathologies [1]
The initial response of cells to low oxygen is largely mediated through actions of the hypoxia inducible factor (HIF) family of proteins
Abundant data support the view that the activation of stress inducible factors such as heat shock factor 1 (HSF1), and the subsequent expression of cytoprotective heat shock proteins, have critical roles in cell survival during tissue reoxygenation
Summary
A low tissue oxygen concentration, followed by the reintroduction of oxygen, gives rise to a phenomenon known as ischemia/ reperfusion injury, and is central to the progression of numerous human pathologies [1]. Cells have mechanisms to ameliorate the effects of resulting damage, the harmful intracellular conditions accompanying IR often override these defenses, causing necrotic or apoptotic cell death. This has devastating consequences for tissues of limited regenerative ability, such as the brain and retina [2,3]. Further understanding of protective pathways and cellular responses to ischemia/reperfusion injury may lead to development of improved or novel clinical therapies
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