Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

Liu, B.; Yi, D.; Li, S.; Ramirez, K.; Xia, X.; Cao, Y.; Zhao, H.; Tripathi, A.; Qiu, S.; Kala, M.; Rafikov, R.; Gu, H.; Perez, V. d. j.; Lemay, S.-E.; Glembotski, C. C.; Knox, K. S.; Kalinichenko, V. V.; Bonnet, S.; Fallon, M. B.; Boucherat, O.; Dai, Z.

doi:10.1101/2024.02.11.579846

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bioRxiv · 10.1101/2024.02.11.579846

Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) of Egln1Tie2Cre (CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of both Fabp4 and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed that Fabp4/5 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2 expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

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Liu, B., Yi, D., Li, S., Ramirez, K., Xia, X., Cao, Y., Zhao, H., Tripathi, A., Qiu, S., Kala, M., Rafikov, R., Gu, H., Perez, V. d. j., Lemay, S.-E., Glembotski, C. C., Knox, K. S., Kalinichenko, V. V., Bonnet, S., Fallon, M. B., Boucherat, O., Dai, Z.. 2024-02-11. Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension. https://doi.org/10.1101/2024.02.11.579846

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