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Hsp27 Upregulation by HIF-1 Signaling Offers Protection against Retinal Ischemia in Rats

¹From the Hewitt Laboratory of the Ola B. Williams Glaucoma Center, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina; the ²Department of Pathology and Anatomy, University of North Texas Health Science Center, Forth Worth, Texas; and the ³Department of Cell Biology, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.

PURPOSE. Previous work from the authors’ laboratory has shown that Hsp27 is specifically upregulated after retinal ischemic preconditioning (IPC), and this upregulation acts as a key cytoprotective factor in preventing retinal ischemic damage. The regulatory mechanisms involved in the upregulation of Hsp27 after IPC are unknown. The purpose of this study was to explore the transcriptional events responsible for the upregulation of Hsp27 after IPC.

METHODS. CoCl₂ was used to test for Hsp27 expression after hypoxic stimulus. The promoter and first intron regions of the human Hsp27 gene were cloned by PCR and characterized by deletion analysis by using a reporter assay. In vitro results were then applied to an in vivo model of retinal ischemia to determine whether CoCl₂ upregulates rHsp27 and protects the retina from ischemic injury.

RESULTS. CoCl₂ upregulated Hsp27 in cultured retinal neurons. Promoter–intron reporter assays using various DNA deletion constructs indicated that several HIF-1 binding sites were necessary for CoCl₂-induced expression of the Hsp27 gene. Furthermore, CoCl₂ upregulated Hsp27 in the rat retina and protected the rat retina from ischemic injury.

CONCLUSIONS. These data provide evidence that Hsp27 is regulated by hypoxic signaling through HIF-1 activation and support the idea that an early event in IPC is the activation of HIF-1. These findings are significant, because this is the first time HIF-1 activation has been associated with the protective effects of IPC and with Hsp27 upregulation.

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