Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding protein 4 (FABP-4), fibroblast growth factor -21 (FGF-21), adiponectin, and the mRNA levels of FABP-4, FGF-21, and peroxisome proliferator-activated receptor γ (PPARγ) in lung tissue of patients with idiopathic PH and healthy controls. We also evaluated lung and adipose tissue expression of these mediators in the three most commonly used experimental rodent models of pulmonary hypertension. Circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in PH patients compared to controls and the mRNA levels of these regulators and PPARγ were also significantly increased in human PH lungs and in the lungs of rats with experimental PH compared to controls. These findings were coupled with increased levels of adipose tissue mRNA of genes related to glucose uptake, glycolysis, tricarboxylic acid cycle, and fatty acid oxidation in experimental PH. Our results support that metabolic alterations in human PH are recapitulated in rodent models of the disease and suggest that adipose tissue may contribute to PH pathogenesis.

The role of stress granules (SGs) in pulmonary arterial hypertension (PAH) is unknown. We hypothesized that SG formation contributes to abnormal vascular phenotypes, and cardiac and skeletal muscle dysfunction in PAH. Using the rat Sugen/hypoxia (SU/Hx) model of PAH, we demonstrate the formation of SG puncta and increased expression of SG proteins compared to control animals in lungs, right ventricles, and soleus muscles. Acetazolamide (ACTZ) treatment ameliorated the disease and reduced SG formation in all of these tissues. Primary pulmonary artery smooth muscle cells (PASMCs) from diseased animals had increased SG protein expression and SG number after acute oxidative stress and this was ameliorated by ACTZ. Pharmacologic inhibition of SG formation or genetic ablation of the SG assembly protein (G3BP1) altered the SU/Hx-PASMC phenotype by decreasing proliferation, increasing apoptosis and modulating synthetic and contractile marker expression. In human PAH lungs, we found increased SG puncta in pulmonary arteries compared to control lungs and in human PAH-PASMCs we found increased SGs after acute oxidative stress compared to healthy PASMCs. Genetic ablation of G3BP1 in human PAH-PASMCs resulted in a phenotypic switch to a less synthetic and more contractile phenotype. We conclude that increased SG formation in PASMCs and other tissues may contribute to PAH pathogenesis.