Mutual promotion of FGF21 and PPARγ attenuates hypoxia-induced pulmonary hypertension

Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPAR gamma in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPAR gamma agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPAR gamma in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPAR gamma in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPAR gamma levels. These changes were reversed by exogenous FGF21 and a PPAR gamma agonist and were further enhanced by a PPAR gamma antagonist. The hypoxia-induced decrease in beta-klotho (KLB) expression was improved by the PPAR gamma agonist and further reduced by the PPAR gamma antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPAR gamma coactivator-1 alpha (PGC-1 alpha) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPAR gamma expression, and the PPAR gamma-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPAR gamma mutually promote each other's expression in HPH via the AMPK/PGC-1 alpha pathway and KLB protein.