Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2

Nanduri R. Prabhakar, Gregg L. Semenza

Research output: Contribution to journalReview article

Abstract

Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O2-regulated HIF-1αor HIF-2αsubunit and a constitutively expressed HIF-1βsubunit. Induction of HIF activity under conditions of reduced O2 αvailability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2αre essential for acute O2 sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology.

Original languageEnglish (US)
Pages (from-to)967-1003
Number of pages37
JournalPhysiological reviews
Volume92
Issue number3
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2'. Together they form a unique fingerprint.

  • Cite this