Research ArticlePhysiology

PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress

Sci. Signal.  03 May 2016:
Vol. 9, Issue 426, pp. ra44
DOI: 10.1126/scisignal.aaf2753

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PERKing blood flow during ischemia

Oxygen deprivation of tissues occurs both physiologically, such as during exercise, and pathologically, such as during stroke or heart attack. The oxygen deprivation that occurs during ischemia causes endoplasmic reticulum (ER) stress, during which most mRNA translation is inhibited to conserve cellular resources. But in ischemic muscles, some mRNAs are translated through an alternative mechanism. These include those encoding VEGF and FGF-2, factors that stimulate blood vessel formation. Philippe et al. found that ER stress in cells and in mice activated the translation of the mRNAs for VEGF and FGF-2 through the alternative mechanism. The kinase PERK, which is activated during ER stress, mediated this translational activation. Administration of a PERK inhibitor to mice before ischemia prevented the translation of the mRNAs for VEGF and FGF-2, raising the possibility that PERK manipulation could be used to increase blood flow in ischemic tissues.

Abstract

Angiogenesis is induced by various conditions, including hypoxia. Although cap-dependent translation is globally inhibited during ischemia, the mRNAs encoding two important proangiogenic growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2), are translated at early time points in ischemic muscle. The translation of these mRNAs can occur through internal ribosome entry sites (IRESs), rather than through cap-dependent translation. Hypoxic conditions also induce the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, leading us to assess the interplay between hypoxia, ER stress, and IRES-mediated translation of FGF-2 and VEGF. We found that unlike cap-dependent translation, translation through FGF-2 and VEGF IRESs was efficient in cells and transgenic mice subjected to ER stress–inducing stimuli. We identified PERK, a kinase that is activated by ER stress, as the driver of VEGF and FGF-2 IRES–mediated translation in cells and in mice expressing IRES-driven reporter genes and exposed to hypoxic stress. These results demonstrate the role of IRES-dependent translation in the induction of the proangiogenic factors VEGF and FGF-2 in response to acute hypoxic stress. Furthermore, the PERK pathway could be a viable pharmacological target to improve physiological responses to ischemic situations.

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