Abstract Body (Do not enter title and authors here): Background: Valine, leucine, and isoleucine are the branched amino acids (BCAA). Elevated BCAAs predict worse outcomes in several cardiovascular diseases with metabolic origins, but the role of BCAAs in pulmonary arterial hypertension (PAH) remains unclear. Moreover, the effects of BCAAs on the emerging lung-liver axis are unexplored.
Methods: The effects of small molecule (BT2) activation of BCAA catabolism and a low BCAA diet were evaluated in monocrotaline rats. Multi-omics analyses of the lung and liver were conducted in the BT2 arm. Confocal microscopy evaluated hepatocyte nuclear size in rodents and humans with PAH. Human livers were subjected to proteomic analysis. Human single nucleotide polymorphisms (SNPs) associated with elevated BCAAs and their relationship with PAH were investigated in the BioVU database.
Results: Proteomics and metabolomics profiling demonstrated BT2 restructured lung fat metabolism, which increased exercise capacity, reduced PAH severity, and improved RV function. A low BCAA diet also mitigated PAH severity and improved RV function. Pathological hepatic shear stress phenotypes induced by RV dysfunction (nuclear hypertrophy, AKT signaling, electron transport chain (ETC) homeostasis, and ceramide accumulation) were blunted by BT2. Human PAH livers partially phenocopied the rodent hepatic shear stress phenotype (nuclear enlargement, AKT activation, and ETC protein downregulation). Finally, patients harboring SNP rs117643180 had increased risk of PAH.
Conclusion: Rodent and human data link altered BCAA catabolism to the pathogenic lung-liver axis in PAH.