%0 Journal Article
%T Mutual promotion of FGF21 and PPAR¦Ă attenuates hypoxia
%A Gexiang Cai
%A Jingjing Liu
%A Kate Huang
%A Liangxing Wang
%A Lihuang Su
%A Manxiang Li
%A Meibin Wang
%A Mengsi Cai
%A Xiaoying Huang
%A Xiuchun Li
%J Experimental Biology and Medicine
%@ 1535-3699
%D 2019
%R 10.1177/1535370219828692
%X Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor ¦Ă (PPAR¦Ă), 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¦Ă 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¦Ă agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPAR¦Ă in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPAR¦Ă 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¦Ă levels. These changes were reversed by exogenous FGF21 and a PPAR¦Ă agonist and were further enhanced by a PPAR¦Ă antagonist. The hypoxia-induced decrease in ¦Â-klotho (KLB) expression was improved by the PPAR¦Ă agonist and further reduced by the PPAR¦Ă antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPAR¦Ă coactivator-1¦Á (PGC-1¦Á) 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¦Ă expression, and the PPAR¦Ă-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¦Ă mutually promote each otherˇŻs expression in HPH via the AMPK/PGC-1¦Á pathway and KLB protein. In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPAR¦Ă in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPAR¦Ă mutually promote each otherˇŻs expression via the AMPK/PGC-1¦Á pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies
%K Fibroblast growth factor 21
%K peroxisome proliferator-activated receptor ¦Ă
%K hypoxia
%K pulmonary hypertension
%K pulmonary arterial smooth muscle cell
%K collagen
%U https://journals.sagepub.com/doi/full/10.1177/1535370219828692