Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy

SIMPLE SUMMARY: In this review paper, we discuss potential new therapies for ischemic heart disease (IHD), a leading cause of death and disability around the world. IHD results from a lack of oxygen supply to the heart muscle, often due to blocked or narrowed blood vessels. One key factor in IHD is the dysfunction of cells lining blood vessels, called endothelial cells. In response to low oxygen levels, these cells activate proteins called hypoxia-inducible factors (HIFs), which help regulate various processes related to cardiovascular diseases. In particular, we focus on HIF2α, which is mainly found in endothelial cells, and its partner ARNT, both of which play crucial roles in IHD development. Our review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cells, their roles in inflammation and maintaining blood vessel integrity, and their involvement in IHD. We explore how these proteins work together and how their activity can be controlled using drugs. In conclusion, targeting HIF2α and ARNT in endothelial cells could offer promising new approaches for treating IHD, ultimately helping to improve the quality of life for millions of people affected by this debilitating condition. ABSTRACT: Ischemic heart disease (IHD) is a major cause of mortality and morbidity worldwide, with novel therapeutic strategies urgently needed. Endothelial dysfunction is a hallmark of IHD, contributing to its development and progression. Hypoxia-inducible factors (HIFs) are transcription factors activated in response to low oxygen levels, playing crucial roles in various pathophysiological processes related to cardiovascular diseases. Among the HIF isoforms, HIF2α is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFβ, also known as ARNT, is the obligate binding partner of HIFα subunits and is necessary for HIFα’s transcriptional activity. ARNT itself plays an essential role in the development of the cardiovascular system, regulating angiogenesis, limiting inflammatory cytokine production, and protecting against cardiomyopathy. This review provides an overview of the current understanding of HIF2α and ARNT signaling in endothelial cell function and dysfunction and their involvement in IHD pathogenesis. We highlight their roles in inflammation and maintaining the integrity of the endothelial barrier, as well as their potential as therapeutic targets for IHD.