A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cellular Physiology

Background:

• Myocardial infarction (MI) impairs cardiac microvascular endothelial barrier function, increasing leakage and inflammation, which drives heart failure progression.
• The role of Hypoxia-Inducible Factor 2 alpha (HIF2α) in endothelial cells during MI remains unclear, despite its expression under hypoxia.

Approach:

• Generated mice with cardiac-specific HIF2α deletion using an inducible Cre system (Cdh5Cre-ERT2).
• Inducible cardiac-specific HIF2α deletion was induced, followed by left anterior descending (LAD) artery ligation to model MI.
• Investigated the effects of HIF2α deletion on endothelial barrier function, inflammation, cardiac function, and remodeling in vivo and in human cardiac microvascular endothelial cells (CMVECs) in vitro.

Key Points:

• Cardiac-specific HIF2α deletion in mice led to increased mortality, vascular leakage, inflammation, worsened cardiac function, and exacerbated remodeling post-MI.
• Loss of endothelial HIF2α in CMVECs reduced barrier integrity, increased cell death, and elevated inflammatory markers like IL6.
• Overexpression of ARNT, a HIF2α partner, reversed these effects, while ARNT deletion increased CMVEC permeability.
• ARNT, not HIF2α, directly binds the IL6 promoter to suppress IL6 expression.

Conclusions:

• Endothelial HIF2α plays a critical protective role in response to cardiac ischemia during myocardial infarction.
• The HIF2α/ARNT axis acts as a transcriptional repressor of inflammatory genes like IL6, crucial for maintaining endothelial barrier function.
• This axis represents a novel therapeutic target for mitigating heart failure following myocardial infarction.