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.
Highlights
Pulmonary Arterial Hypertension (PAH), a progressive and often fatal disease that primarily affects the pulmonary circulation and right ventricle of the heart, is increasingly recognized as a systemic disorder in which inflammatory and metabolic derangements may play a pathogenetic role [1,2,3]
ExPPARγ were previously reported in non-adipose tissues, we evaluated their mRNA expression in the lungs of Idiopathic Pulmonary Arterial Hypertension (IPAH) patients and normal controls
We further evaluated the expression of fatty acid binding protein 4 (FABP-4) in pulmonary arteries and found no differences between IPAH subjects and controls
Summary
Pulmonary Arterial Hypertension (PAH), a progressive and often fatal disease that primarily affects the pulmonary circulation and right ventricle of the heart, is increasingly recognized as a systemic disorder in which inflammatory and metabolic derangements may play a pathogenetic role [1,2,3]. A metabolically active endocrine organ, which is implicated in cardiometabolic homeostasis, may be involved in PAH pathogenesis through production and Adipose tissue, a metabolically active endocrine organ, which is implicated in cardiometabolic homeostasis, may be involved in PAH pathogenesis through production and secretion of bioactive mediators known as adipokines that act locally and systemically These mediators may regulate several physiologic functions including, but not limited to, glucose and lipid metabolism, insulin sensitivity, and inflammation [11]. Fatty acid-binding previous reports referring to the role of specific adipokines in PAH [12,13] we assumed the protein-4 growth factor-21 in (FGF-21), existence (FABP-4), of adipose Fibroblast tissue metabolic implication. In order to investigate the above hypothesis, we studied a panel of primarily adipose experimental pulmonary hypertension in rats and evaluated the metabolic state of aditissue-derived or therein implicated metabolic regulators including Fatty acid-binding pose tissue(FABP-4), by assessing mRNAgrowth levels of genes involved glycolysis, the protein-4. Circulating Concentrations of FABP-4, FGF-21, and Adiponectin are Significantly Elevated
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