Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension.
Bin LiuDan YiShuai LiKarina RamirezXiaomei XiaYanhong CaoHanqiu ZhaoAnkit TripathiShenfeng QiuMrinalini KalaRuslan RafikovHaiwei GuVinicio A de Jesus PerezSarah-Eve LemayChristopher C GlembotskiKenneth S KnoxSebastien BonnetVladimir V KalinichenkoYou-Yang ZhaoMichael B FallonOlivier BoucheratZhiyu DaiPublished in: bioRxiv : the preprint server for biology (2024)
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 Egln1 Tie2Cre (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 ( Egln1 Tie2Cre /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-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.
Keyphrases
- pulmonary hypertension
- single cell
- rna seq
- pulmonary arterial hypertension
- heart failure
- binding protein
- endothelial cells
- pulmonary artery
- end stage renal disease
- newly diagnosed
- ejection fraction
- left ventricular
- fatty acid
- poor prognosis
- gene expression
- dna methylation
- high throughput
- type diabetes
- mycobacterium tuberculosis
- cell death
- blood pressure
- long non coding rna
- coronary artery
- skeletal muscle
- oxidative stress
- atrial fibrillation
- high glucose
- diabetic rats
- reactive oxygen species
- polycyclic aromatic hydrocarbons
- data analysis