HIF‑1α in myocardial ischemia‑reperfusion injury (Review)

Abstract

Myocardial ischemia‑reperfusion injury (MIRI) is a severe injury to the ischemic myocardium following the recovery of blood flow. Currently, there is no effective treatment for MIRI in clinical practice. Over the past two decades, biological studies of hypoxia and hypoxia‑inducible factor‑1α (HIF‑1α) have notably improved understanding of oxygen homeostasis. HIF‑1α is an oxygen‑sensitive transcription factor that mediates adaptive metabolic responses to hypoxia and serves a pivotal role in MIRI. In particular, previous studies have demonstrated that HIF‑1α improves mitochondrial function, decreases cellular oxidative stress, activates cardioprotective signaling pathways and downstream protective genes and interacts with non‑coding RNAs. The present review summarizes the roles and associated mechanisms of action of HIF‑1α in MIRI. In addition, HIF‑1α‑associated MIRI intervention, including natural compounds, exosomes, ischemic preconditioning and ischemic post‑processing are presented. The present review provides evidence for the roles of HIF‑1α activation in MIRI and supports its use as a therapeutic target.

Keywords: hypoxia‑inducible factor‑1α; ischemic heart disease; myocardial ischemia‑reperfusion injury; mitochondrial function.

Figure 1.

Schematic illustration of the domain structure of HIF-1α. HIF-1α consists of a bHLH motifs and a PAS domain in the NH₂-terminal, which are necessary for heterodimerization and DNA binding to hypoxia response elements. The two TADs, which stimulate transcription, are present in the COOH-terminal of HIF-1α. TAD-C interacts with coactivators such as CREB-binding protein/p300 to activate gene transcription. HIF-1α also contains an ODDD, which promotes proteasomal degradation of HIF-1α by PHD-containing enzymes and factor inhibiting HIF. HIF-1α, hypoxia-inducible factor-1α; bHLH, basic helix-loop-helix; PAS, Per-ARNT-Sim homology; TAD, transactivation domains; TAD-N, transactivation domain N terminal; TAD-C, transactivation domain C terminal; ODD, oxygen-dependent-degradation; PHD, prolyl hydroxylase domain.

Figure 2.

Oxygen-dependent regulation of HIF-1α. In normoxic conditions, HIF-1α protein is hydroxylated by prolyl hydroxylases PHD1, PHD2, and PHD3. Hydroxylated HIF-1α is recognized by VHL and degraded by the ubiquitin-proteasome pathway. In hypoxic conditions, HIF-1α accumulates and translocates to the nucleus where it binds to ARNT to form a heterodimeric complex that binds to the promoter region of the HRE. CBP/p300 recruitment induces transcription of downstream target genes. HIF-1α, hypoxia-inducible factor-1α; PHD, prolyl hydroxylases; VHL, von Hippel-Lindau; ARNT, aryl hydrocarbon receptor nuclear translocator; HRE, hypoxia-response element; CBP, CREB-binding protein; EPO, erythropoietin; iNOS, inductible nitric oxide synthase; VEGF, vascular endothelial cell growth factor; PHD, prolyl hydroxylase domain.

Figure 3.

Pathophysiological mechanisms involved in MIRI. Oxidative stress, inflammatory responses, mitochondrial damage and calcium overload, as well as hypoxia-associated factors contribute to the pathophysiology of MIRI. MIRI, myocardial ischemia-reperfusion injury.

Figure 4.

Roles of HIF-1α in MIRI. The upward-facing arrow indicates enhancement. The downward-facing arrow indicates inhibition. MIRI, myocardial ischemia reperfusion injury; HIF-1α, hypoxia-inducible factor-1α; miRNA, microRNA; lncRNA, long non-coding RNA; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; iNOS, induced nitric oxide synthase; IGF2, insulin-like growth factor 2; GLUT, glucose transporter; Nox, NADPH oxidase; Nrf2, nuclear factor erythroid 2-related factor 2; SOD, superoxide dismutase; glutathione; ROS, reactive oxygen species; RNS, reactive nitrogen species, RNS.