Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension

Overview

Journal bioRxiv

Date 2024 Feb 19

PMID 38370670

Authors

Bin Liu

Dan Yi

Shuai Li

Karina Ramirez

Xiaomei Xia

Yanhong Cao

Hanqiu Zhao

Ankit Tripathi

Shenfeng Qiu

Mrinalini Kala

Ruslan Rafikov

Haiwei Gu

Vinicio De Jesus Perez

Sarah-Eve Lemay

Christopher C Glembotski

Kenneth S Knox

Sebastien Bonnet

Vladimir V Kalinichenko

You-Yang Zhao

Michael B Fallon

Olivier Boucherat

Zhiyu Dai

Affiliations

Soon will be listed here.

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 (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 and 5 in CKO mice ( ,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 deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2α 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.

References

Lei Q, Yu Z, Li H, Cheng J, Wang Y . Fatty acid-binding protein 5 aggravates pulmonary artery fibrosis in pulmonary hypertension secondary to left heart disease via activating wnt/β-catenin pathway. J Adv Res. 2022; 40:197-206. PMC: 9481948. DOI: 10.1016/j.jare.2021.11.011. View

Storch J, Corsico B . The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr. 2008; 28:73-95. DOI: 10.1146/annurev.nutr.27.061406.093710. View

Stacher E, Graham B, Hunt J, Gandjeva A, Groshong S, McLaughlin V . Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012; 186(3):261-72. PMC: 3886716. DOI: 10.1164/rccm.201201-0164OC. View

Chandel N, McClintock D, Feliciano C, Wood T, Melendez J, Rodriguez A . Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem. 2000; 275(33):25130-8. DOI: 10.1074/jbc.M001914200. View

Cao Y, Zhang X, Wang L, Yang Q, Ma Q, Xu J . PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension. Proc Natl Acad Sci U S A. 2019; 116(27):13394-13403. PMC: 6613097. DOI: 10.1073/pnas.1821401116. View

Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J . Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 2001; 15(2):427-38. DOI: 10.1096/fj.00-0343com. View

Tang H, Babicheva A, McDermott K, Gu Y, Ayon R, Song S . Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Am J Physiol Lung Cell Mol Physiol. 2017; 314(2):L256-L275. PMC: 5866501. DOI: 10.1152/ajplung.00096.2017. View

Elmasri H, Ghelfi E, Yu C, Traphagen S, Cernadas M, Cao H . Endothelial cell-fatty acid binding protein 4 promotes angiogenesis: role of stem cell factor/c-kit pathway. Angiogenesis. 2012; 15(3):457-68. PMC: 3590918. DOI: 10.1007/s10456-012-9274-0. View

Liu M, Zhou M, Bao Y, Xu Z, Li H, Zhang H . Circulating adipocyte fatty acid-binding protein levels are independently associated with heart failure. Clin Sci (Lond). 2012; 124(2):115-22. DOI: 10.1042/CS20120004. View

10.

Papathanasiou A, Spyropoulos F, Michael Z, Joung K, Briana D, Malamitsi-Puchner A . Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension. Int J Mol Sci. 2021; 22(3). PMC: 7867052. DOI: 10.3390/ijms22031435. View

11.

Weatherald J, Huertas A, Boucly A, Guignabert C, Taniguchi Y, Adir Y . Association Between BMI and Obesity With Survival in Pulmonary Arterial Hypertension. Chest. 2018; 154(4):872-881. DOI: 10.1016/j.chest.2018.05.006. View

12.

Liu B, Peng Y, Yi D, Machireddy N, Dong D, Ramirez K . Endothelial PHD2 deficiency induces nitrative stress suppression of caveolin-1 in pulmonary hypertension. Eur Respir J. 2022; 60(6). PMC: 9791795. DOI: 10.1183/13993003.02643-2021. View

13.

Maeda K, Cao H, Kono K, Gorgun C, Furuhashi M, Uysal K . Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metab. 2005; 1(2):107-19. DOI: 10.1016/j.cmet.2004.12.008. View

14.

Hwangbo C, Wu J, Papangeli I, Adachi T, Sharma B, Park S . Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. Sci Transl Med. 2017; 9(407). PMC: 5703224. DOI: 10.1126/scitranslmed.aad4000. View

15.

Hotamisligil G, Bernlohr D . Metabolic functions of FABPs--mechanisms and therapeutic implications. Nat Rev Endocrinol. 2015; 11(10):592-605. PMC: 4578711. DOI: 10.1038/nrendo.2015.122. View

16.

Fuseya T, Furuhashi M, Matsumoto M, Watanabe Y, Hoshina K, Mita T . Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury. J Am Heart Assoc. 2017; 6(9). PMC: 5634290. DOI: 10.1161/JAHA.117.006377. View

17.

Dai Z, Zhu M, Peng Y, Jin H, Machireddy N, Qian Z . Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension. Am J Respir Crit Care Med. 2018; 198(6):788-802. PMC: 6222462. DOI: 10.1164/rccm.201709-1835OC. View

18.

Boucherat O, Yokokawa T, Krishna V, Kalyana-Sundaram S, Martineau S, Breuils-Bonnet S . Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension. Nat Cardiovasc Res. 2024; 1(8):748-760. DOI: 10.1038/s44161-022-00113-w. View

19.

Kalucka J, de Rooij L, Goveia J, Rohlenova K, Dumas S, Meta E . Single-Cell Transcriptome Atlas of Murine Endothelial Cells. Cell. 2020; 180(4):764-779.e20. DOI: 10.1016/j.cell.2020.01.015. View

20.

Li X . VEGF-B: a thing of beauty. Cell Res. 2010; 20(7):741-4. PMC: 2943826. DOI: 10.1038/cr.2010.77. View