HIF and pulmonary vascular responses to hypoxia

Abstract

In the lung, acute reductions in oxygen lead to hypoxic pulmonary vasoconstriction, whereas prolonged exposures to hypoxia result in sustained vasoconstriction, pulmonary vascular remodeling, and the development of pulmonary hypertension. Data from both human subjects and animal models implicate a role for hypoxia-inducible factors (HIFs), oxygen-sensitive transcription factors, in pulmonary vascular responses to both acute and chronic hypoxia. In this review, we discuss work from our laboratory and others supporting a role for HIF in modulating hypoxic pulmonary vasoconstriction and mediating hypoxia-induced pulmonary hypertension, identify some of the downstream targets of HIF, and assess the potential to pharmacologically target the HIF system.

Keywords: digoxin; hypoxia inducible factor; hypoxic pulmonary vasoconstriction; pulmonary hypertension.

Fig. 1.

Schematic detailing the regulation of hypoxia-inducible factor 1 (HIF-1). A: under normoxic conditions, HIF-1α protein levels are regulated by prolyl hydroxylase domain (PHD) proteins and von Hipple-Lindau (VHL) protein, targeting the protein for degradation. B: transactivation of HIF is controlled by factor inhibiting HIF-1 (FIH-1), an asparaginyl hydroxylase. Hydroxylation of the asparagine residue prevents cofactor binding. During hypoxia, HIF-1α escapes both prolyl (Pro) and asparaginyl (Asn) hydroxylation, leading to protein accumulation, nuclear translocation, and formation and binding of the transcriptional complex to target genes. Ub, ubiquitin; CBP, CREB binding protein; HRE, hypoxia response element.

Fig. 2.

Proposed role of HIF-1 in hypoxic pulmonary hypertension. Initially, hypoxia induces the synthesis and release of endothelin-1 (ET-1) from pulmonary endothelial and arterial smooth muscle cells (PASMCs). ET-1 binds to receptors on the PASMCs, increasing Ca²⁺ sensitivity of the contractile apparatus and upregulating HIF-1α, which induces ET-1 transcription and results in a feedforward mechanism to augment HIF activation. Downstream targets of HIF-1 include voltage-gated K⁺ channels (including Kv1.5 and Kv2.1), Na⁺/H⁺ exchanger isoform 1 (NHE1), and canonical transient receptor potential (TRPC) proteins (TRPC1 and TRPC6), which coordinate to regulate PASMC contraction, growth/survival, and migration. ppET, prepro-endothelin; [Ca²⁺]_i, intracellular Ca²⁺ concentration.