Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension

Abstract

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.

Relaxin-2 as a Potential Biomarker in Cardiovascular Diseases

“…There exists a growing interest in the study of bioactive molecules, such as hormones or adipokines, as prognostic factors for the development of hypertension [ 144 , 145 ]. The hormone relaxin-2 is also considered an adipokine implicated in the protection against cardiometabolic diseases, being able to modulate inflammation, blood pressure and angiogenesis, induce vasodilatation, improve endothelial dysfunction during hypertension, and regulate fibrosis and ECM remodelling, two processes that predispose to hypertensive heart disease [ 146 , 147 , 148 , 149 , 150 ].…”

Research Progress of Fibroblast Growth Factor 21 in Fibrotic Diseases

“…The data shows that FGF21 suppressed inflammation and apoptosis, which provides a possibility for treating lipopolysaccharide-induced acute lung injury [ 106 ] via the inhibition of the TLR4/Myd88/NF- κ B signaling pathway. In pulmonary hypertension, interventional studies show that exogenous FGF21 upregulates PPAR γ expression to improve prognosis by AMPK-related pathway [ 107 , 108 ]. As is widely known, the nuclear factor erythroid2-related factor2 (Nrf-2) signal pathway participates in redox homeostasis [ 109 ], which suppresses oxidative stress.…”

Fatty Acid Metabolism in Endothelial Cell

“…In both heritable pulmonary arterial hypertension (HPAH) and right ventricular hypertrophy mouse model, FA metabolic genes are abnormally changed due to FA oxidation deficiency caused lipid disposition [179,180]. In addition, circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in human PH lungs and experimental PH rat lungs [183]. Indeed, increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV, which reflects a shift towards increased FA oxidation and glycolysis associated with RV failure in PAH [184].…”