Hypoxia-induced signaling in the cardiovascular system

Abstract

Low oxygen (O2) levels are a naturally occurring feature of embryonic development, adult physiology, and diseases such as those of the cardiovascular system. Although many responses to O2 deprivation are mediated by hypoxia-inducible factors (HIFs), researchers are finding a growing number of HIF-independent pathways that promote O2 conformance and hypoxia tolerance. Here, we describe HIF-independent responses and how they impact cardiovascular tissue homeostasis.

Figure 1

Hypoxia-inducible factor (HIF)-dependent transcriptional responses to hypoxia. In response to O₂ deprivation, HIFs, consisting of an alpha and a beta (ARNT) subunit, are activated and bind to hypoxia response elements (HREs) scattered throughout the genome. HIFs stimulate the expression of approximately 200 target genes that mediate hypoxic adaptations and are involved in energy metabolism, cell growth or apoptosis, angiogenesis, cell motility, and the establishment of the extracellular matrix.

Figure 2

Hypoxic regulation of mRNA translation and its roles in cellular tolerance to low O₂ and ischemia/reperfusion. Schematic diagrams for signaling pathways activated during hypoxia that result in (a) mTORC1 inhibition or (b) activation of the unfolded protein response (UPR). (c) Ischemic preconditioning, a brief exposure to ischemia, provides a powerful temporal protection against more prolonged and deleterious ischemic/reperfusion injury. Ischemic preconditioning results in the induction of an acute protein synthesis inhibition (PSI) after ischemia/reperfusion, rather than a persistent protein synthesis inhibition in its absence (see text for more details). Other abbreviations: 4E-BP1, eIF4E-binding protein 1; AMPK, AMP-activated kinase; ATF4, activating transcription factor 4; CHOP, c/ebp-homologous protein; eIF, eukaryotic initiation factor; GADD34, DNA-damage-inducible gene 34; IRE1, inositol-requiring 1; mTORC, mammalian target of rapamycin complex; PERK, pancreatic eIF2-alpha kinase; PML, promyelocytic leukemia; PP1, protein phosphatase 1; XBP1, X box–binding protein 1.

Figure 3

Hypoxic effects on mTORC1. (a) In many cells, hypoxia inhibits mTORC1 activity either directly or indirectly, resulting in decreased phosphorylation of the downstream targets of mTORC1, 4E-BP1 and p70^S6K. This results in an overall decrease in protein synthesis capacity and subsequent decreases in proliferation and cell growth. Many cells likely utilize this response to adapt to the hypoxic insult and await a return to homeostatic O₂ levels. (b) Other cells, including cells of the cardiovascular system, respond to hypoxia with an enhancement of mTORC1 activity. mTORC1 activation increases 4E-BP1 and p70^S6K phosphorylation, resulting in potentially increased protein synthesis, cell growth, and proliferation. This response may be programmed to occur upon hypoxia-induced vascular remodeling or during recovery from ischemia. Tumor cells may utilize a similar strategy through an unknown mediator or alternatively via oncogenic signaling, overcoming hypoxic inhibition.

Figure 4

Theoretical model and potential mechanisms for the selective translation of individual mRNAs whose protein products may contribute to a cardioprotective phenotype. Cellular stresses such as hypoxia can lead to the selective translation of mRNAs involved in the integrated stress response, angiogenesis, antiapoptotic factors, and cell cycle inhibitors. These factors may be involved in the adaptation of cardiac tissue to hypoxic stress. The mechanism(s) for the hypoxia-mediated preferential translation of individual mRNAs is largely unknown, but contributing regulatory pathways are shown. Of note, both 4E-BP1 and 4E-T can inhibit eIF4E activity in O₂-starved cells. Abbreviations: 4E-BP1, eIF4E-binding protein 1; ATF4, activating transcription factor 4; eIF, eukaryotic initiation factor; IRES, internal ribosome entry site; miRNA, microRNA; uORF, upstream open reading frame; UTR-BP, untranslated region-binding protein.