Hypoxia-Inducible Factor-1 in Arterial Disease: A Putative Therapeutic Target

Veeru      Kasivisvanathan; Joseph      Shalhoub; Chung      S. Lim; Amanda      C. Shepherd; Ankur      Thapar; Alun      H. Davies

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a nuclear transcription factor that is upregulated in hypoxia and coordinates the adaptive response to hypoxia by driving the expression of over 100 genes. In facilitating tissues to adapt to hypoxia, HIF-1 may have a role in reducing the cellular damage induced by ischaemia, such as that seen in peripheral arterial disease (PAD), or following acute ischaemic insults such as stroke and myocardial infarction. This therefore raises the possibility of HIF-1 modulation in such contexts to reduce the consequences of ischaemic injury. HIF1 has further been implicated in the pathogenesis of atherosclerosis, abdominal aortic aneurysm (AAA) formation, pulmonary hypertension and systemic hypertension associated with obstructive sleep apnoea. Through a better understanding of the role of HIF-1 in these disease processes, novel treatments which target HIF-1 pathway may be considered. This review summarises the role of HIF-1 in arterial disease, specifically its role in atherosclerosis, ischaemic heart disease, in-stent restenosis following coronary revascularisation, stroke, PAD, AAA formation, pulmonary artery hypertension and systemic hypertension. The potential for exploiting the HIF-1 signalling pathway in developing therapeutics for these conditions is discussed, including progress made so far, with attention given to studies looking into the use of prolyl-hydroxylase inhibitors.

Keywords: Aortic aneurysm, arterial disease, atherosclerosis, hypertension, hypoxia-inducible factor, ischaemic heart disease, prolyl-hydroxylase inhibitor, stroke, angiogenesis, hypoxia-inducible factor-1, obstructive sleep apnea