FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19

Area of Science:

• Molecular Biology
• Cardiovascular Research
• RNA Biology

Background:

• Pulmonary hypertension (PH) involves complex molecular mechanisms.
• Long non-coding RNAs (lncRNAs) are implicated in PH pathogenesis.
• Fibroblast growth factor 21 (FGF21) shows potential in attenuating hypoxia-induced PH.

Purpose of the Study:

• To investigate the regulatory role of lncRNAs in FGF21-treated PH.
• To elucidate the mechanism by which FGF21 impacts PH via lncRNA modulation.
• To identify specific lncRNAs involved in FGF21's therapeutic effects on PH.

Main Methods:

• RNA sequencing and real-time PCR to identify differentially expressed lncRNAs.
• Gain- and loss-of-function assays to determine H19's role.
• In vivo studies using FGF21 deficiency and H19 overexpression models in mice.
• Western blotting to assess mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway components.

Main Results:

• FGF21 administration significantly upregulated the lncRNA H19 in hypoxia-induced PH.
• FGF21 suppressed pulmonary artery smooth muscle cell proliferation partly via H19 upregulation.
• FGF21 deficiency exacerbated PH, while H19 overexpression reversed these effects in mice.
• H19 inhibited mTORC1 activity by disrupting the mTORC1-EIF4EBP1 interaction.

Conclusions:

• H19 is a key mediator of FGF21's protective effects in PH.
• The FGF21-H19 axis regulates PH through the mTORC1/EIF4EBP1 pathway.
• This study provides a mechanistic basis for FGF21's clinical application in treating PH.