Targeting Endothelial HIF2α/ARNT Expression for Ischemic Heart Disease Therapy

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.

Hypoxia-inducible factor-2α promotes fibrosis in non-alcoholic fatty liver disease by enhancing glutamine catabolism and inhibiting yes-associated protein phosphorylation in hepatic stellate cells

“…HIF-1α and HIF-2α recognise and bind hypoxia response elements to activate the cellular response to hypoxia. However, HIF-1α and HIF-2α have different structures and expression patterns ( 40 – 42 ). In this study, HIF-2α displayed different expression levels and distribution in hepatic tissue from both patients with NASH and mouse models for NASH subjected to persistent hypoxia, compared with those of HIF-1α.…”

Editorial: Special Issue—Understanding and Targeting Heart Failure: From Biology to Therapeutics

“…They showed that manganese porphyrin improved survival, neurologic function recovery, and behavioral performance in animals suffering from cardiac arrest. Ullah et al [4] reviewed the current understanding of HIF2α and ARNT signaling in endothelial cells, their roles in inflammation and maintaining blood vessel integrity, and their involvement in ischemic heart disease. The two studies either provided new therapeutics for cardiac arrest or systematically reviewed the role of the HIF2α and ARNT signaling pathway in endothelial cells, which are helpful for establishing new therapeutics and targets for the development of new treatments for heart failure.…”