Targeting Endothelial HIF2alpha/ARNT Expression for Ischemic Heart Disease Therapy.
Publication Year:
2023
PubMed ID:
37508425
Funding Grants:
Public Summary:
Ischemic heart disease (IHD) is a leading cause of death worldwide, and new treatments are urgently needed. A key problem in IHD is damage to the lining of blood vessels in the heart, called endothelial dysfunction. Proteins called hypoxia-inducible factors (HIFs) help cells respond to low oxygen levels and play important roles in heart disease. One type, HIF2α, is mostly found in the blood vessel lining of the heart and is important in how the disease develops. Another protein, ARNT, works with HIF2α to control gene activity, help blood vessel growth, reduce inflammation, and protect the heart. This review explains how HIF2α and ARNT affect blood vessel health and disease in the heart and discusses their potential as targets for new IHD treatments.
Scientific 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, HIF2alpha is predominantly expressed in cardiac vascular endothelial cells and has a key role in cardiovascular diseases. HIFbeta, also known as ARNT, is the obligate binding partner of HIFalpha subunits and is necessary for HIFalpha'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 HIF2alpha 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.