Farnesyl diphosphate synthase regulated endothelial proliferation and autophagy during rat pulmonary arterial hypertension induced by monocrotaline

Abstract

Background The proliferation ability and autophagy level of pulmonary artery endothelial cells (PAECs) play an important role in promoting the development of pulmonary artery hypertension (PAH), and there is still no effective treatment for PAH. Farnesyl diphosphate synthase (FDPS) is a key enzyme in the mevalonate pathway. The intermediate metabolites of this pathway are closely related to the activity of autophagy-associated small G proteins, including Ras-related C3 botulinum toxin substrate 1 (Rac1). Studies have shown that the mevalonate pathway affects the activation levels of different small G proteins, autophagy signaling pathways, vascular endothelial function, and so on. However, the exact relationship between them is still unclear in PAH. Method In vitro, western blotting and mRFP-GFP-LC3 puncta formation assays were used to observe the expression of FDPS and the level of autophagy in PAECs treated with monocrotaline pyrrole (MCTP). In addition, cell proliferation and migration assays were used to assess the effect of FDPS on endothelial function, and Rac1 activity assays were used to evaluate the effect of Rac1 activation on PAEC autophagy via the PI3K/AKT/mTOR signaling pathway. In vivo, the right heart catheterization method, hematoxylin and eosin (H&E) staining and western blotting were used to determine the effect of FDPS on PAEC autophagy and monocrotaline (MCT)-induced PAH. Results We show that the expression of FDPS is increased in the PAH module in vitro and in vivo, concomitant with the induction of autophagy and the activation of Rac1. Our data demonstrate that inhibition of FDPS ameliorates endothelial function and decreases MCT-induced autophagy levels. Mechanistically, we found that FDPS promotes autophagy, Rac1 activity and endothelial disfunction through the PI3K/AKT/mTOR signaling pathway. Conclusion Our study suggests that FDPS contributes to active small G protein-induced autophagy during MCT-induced PAH, which may serve as a potential therapeutic target against PAH.

Exosomes enriched by miR-429-3p derived from ITGB1 modified Telocytes alleviates hypoxia-induced pulmonary arterial hypertension through regulating Rac1 expression

“…Rac1 was choose for further experiments due to RAC1 activation leads to increased proliferation of PASMCs and contributes to the development of pulmonary vascular remodeling (Fig. 5 B) (Zheng et al 2023 ; Jin et al 2022 ; Dilasser et al 2022 ). The reports results of dual luciferase showed that compared to the Exo-Ve, the luciferase activity of Rac1-WT showed significant inhibition of by Exo-ITGB1, while no difference was observed in the Rac1-MUT (Fig.…”

Farnesyl Diphosphate Synthase (FDPS) Regulates Granulosa Cells Proliferation of Polycystic Ovary Syndrome (PCOS) by Modulating the Rac1/MAPK/ERK signaling

“…Some scholars have reported that DPP4 knockout promotes proliferation and activation of CREB/ aromatase pathway in GCs, thereby alleviating PCOS [39]. Recent accumulated evidence revealed that FDPS has been found to be involved in various biological functions and disease processes, such as FDPS regulates endothelial cell proliferation and autophagy [13]. In consistent with the above results, our research proved FDPS was closely related to the proliferation of GCs that knockdown of FDPS inhibited proliferation of GCs, while overexpression of FDPS promoted proliferation of GCs.…”

“…In particular, FDPS regulate cell growth and survival through GTPase/AKT axis, ERK, and STAT3 [12]. Some studies have found that inhibiting FDPS can reduce the activation of Rac1, which is closely associated with the PI3K/AKT/mTOR pathway [13].In addition, it also has a regulatory role in a variety of diseases, including malignancies (e.g., prostate cancer, glioblastoma) [12,14], cardiac dysfunction [15], pulmonary artery hypertension [13], and diabetes [16]. However, the role of FDPS in PCOS patients is unclear and more research is needed.…”

Epigenetic regulation of programmed cell death in hypoxia-induced pulmonary arterial hypertension

“…Jin et al. demonstrated that farnesyl diphosphate synthase (FDPS) contributes to active small G protein-induced autophagy during PAH ( 35 ). In a separate investigation, it was found that glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, can suppress the proliferation of PASMCs by inhibiting cellular Drp1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) pathways and Atg-5/Atg-7/Beclin-1/LC3β-dependent pathways of autophagy in PAH ( 36 ).…”