Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and...

Area of Science:

• Cardiovascular Research
• Pulmonary Hypertension Pathophysiology
• Molecular Biology

Background:

• Pulmonary arterial hypertension (PAH) is a severe condition marked by vascular remodeling, leading to right heart failure.
• Identifying cellular and molecular drivers of PAH is crucial for developing new treatments.

Purpose of the Study:

• To investigate the role of fatty acid-binding proteins (FABP4 and FABP5) in the development and progression of pulmonary hypertension (PH).
• To evaluate the therapeutic potential of targeting FABP4/5 in PH models.

Main Methods:

• Single-cell RNA sequencing (scRNAseq) and spatial transcriptomics were used to analyze gene expression in mouse models and human samples.
• Genetic deletion of FABP4/5 in a PH mouse model (Egln1 CKO mice).
• Assessment of cardiac function, hemodynamics, and vascular remodeling using echocardiography, catheterization, and histology.

Main Results:

• FABP4 and FABP5 were significantly upregulated in pulmonary endothelial cells (ECs) in PH models and human PAH.
• Plasma FABP4/5 levels correlated with PH severity.
• Genetic deletion of FABP4/5 in mice attenuated PH, reduced vascular remodeling, and prevented right heart failure.
• FABP4/5 inhibition decreased EC glycolysis, ROS, and HIF-2α expression, and altered distal arterial programming.

Conclusions:

• Aberrant FABP4/5 expression in pulmonary ECs contributes to PH pathogenesis by promoting glycolysis and vascular remodeling.
• Targeting FABP4/5 represents a promising therapeutic strategy for treating pulmonary hypertension.