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

Abstract

Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor γ (PPARγ), 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 PPARγ in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPARγ agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPARγ in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPARγ 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 PPARγ levels. These changes were reversed by exogenous FGF21 and a PPARγ agonist and were further enhanced by a PPARγ antagonist. The hypoxia-induced decrease in β-klotho (KLB) expression was improved by the PPARγ agonist and further reduced by the PPARγ antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPARγ coactivator-1α (PGC-1α) 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 PPARγ expression, and the PPARγ-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 PPARγ mutually promote each other’s expression in HPH via the AMPK/PGC-1α pathway and KLB protein. Impact statement 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 PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other’s expression via the AMPK/PGC-1α 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 for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension

“…We did indeed demonstrate increased FGF-21 mRNA expression in lung tissue from patients with IPAH, but whether this contributes to the elevated circulating FGF-21 levels, rather than simply acting in an autocrine manner, remains to be elucidated. Our finding in human IPAH is in contrast with the results of two preclinical studies which demonstrated that hypoxia-induced PH in mice or rats was associated with decreased FGF-21 mRNA expression in lungs and pulmonary arterioles [ 39 ] or decreased circulating FGF-21 serum levels, respectively [ 40 ]. Interventional studies showed that exogenous FGF-21 attenuated hypoxia-induced PH and inflammatory cytokine secretion through enhancing PPARγ expression in rats [ 40 ], attenuated hypoxic pulmonary arterial remodeling and collagen deposition in mice [ 39 ], and ameliorated hypoxia-induced dysfunction in human pulmonary arterial endothelial cells through alleviating endoplasmic reticulum stress [ 41 ].…”

FGF21 attenuates hypoxia‑induced dysfunction and inflammation in HPAECs via the microRNA‑27b‑mediated PPARγ pathway

“…Moreover, PPARγ has been demonstrated to suppress inflammatory cytokine levels in hypoxia-exposed pulmonary artery smooth muscle cells (20). Recently, hypoxia-induced PH was found to be associated with the reductions in PPARγ expression, and the activation of PPARγ attenuated increased pulmonary arterial pressure and right ventricular hypertrophy in hypoxia-exposed mice (9). The aforementioned findings suggest the protective role of PPARγ in PAH.…”

“…Increasing evidence indicates that PPARγ is a potent, protective regulator of PAH (6) and pulmonary artery Ecs (PAECs) (7,8). In addition, a previous study proved that PPARγ activation alleviated hypoxia-induced pulmonary arterial remodeling and collagen deposition in hypoxia-induced PAH (9). However, the role of PPARγ in Ec dysfunction and inflammation in hypoxia-exposed human PAECs (HPAECs) has yet to be fully elucidated.…”

Hypoxia-Induced Adipose Lipolysis Requires Fibroblast Growth Factor 21

“…Previous studies have shown that adipose tissue lipolysis is associated with tissue hypoxia (Mahat et al, 2016), which is a pathophysiological state existing in many disease conditions (Famulla et al, 2012;Plihalova et al, 2016;Zhang et al, 2017). At molecular level, lipolysis and hypoxia have been linked to fibroblast growth factor 21 (FGF21), respectively (Arner et al, 2008;Cai et al, 2019).…”

“…Circulating FGF21 levels have been found to be elevated in patients and experimental animals with various metabolic conditions, such as obesity (Dushay et al, 2010), non-alcoholic fatty liver disease (Kim et al, 2015), and type 2 diabetes (Barb et al, 2019). Besides, previous studies have demonstrated that there was a association between hypoxia and FGF21 regulation in many diseases such as type 2 diabetes with early renal injury (Yu et al, 2019), pulmonary hypertension (Cai et al, 2019), and cerebral disease (Wang et al, 2019). Hypoxic conditions increase the circulating concentrations of FFAs, which are produced from adipose tissue by increased lipolysis (Yin et al, 2009).…”