Our study indicates that dacomitinib inhibited hypoxia-induced cell cycle progression, proliferation, migration, and autophagy of PASMCs, thereby attenuating pulmonary vascular remodeling and development of PAH via the PI3K-AKT-mTOR signaling pathway.
Next, CHD-PAH mouse models were established and treated with restored or depleted Gal-3 to evaluate the systolic pulmonary artery pressure (sPAP) and right ventricular hypertrophy index (RVHI), to determine levels of IL-4, IL-5, IL-13, AKT and p-AKT along with proliferation of pulmonary artery smooth muscle cells (PASMCs).
The aim of this study was to investigate the effect of atorvastatin on pulmonary arterial hypertension (PAH) in rats and to observe its specific regulatory mechanism through the phosphatidylinositol 3-hydroxy kinase/protein kinase B (PI3K/AKT) signaling pathway.
In addition, LY294002, a PI3K inhibitor, reduced the PI3K and p‑Akt protein expression in the PAECs and reversed the effects of miR‑371b‑5p overexpression on the apoptosis of PAECs in rats with monocrotaline‑induced PAH.
Downregulation of STIM2 in PAH-PASMCs reduces the resting [Ca<sup>2+</sup>]<sub>cyt</sub>, whereas overexpression of STIM2 in normal PASMCs increases the resting [Ca<sup>2+</sup>]<sub>cyt</sub> The increased resting [Ca<sup>2+</sup>]<sub>cyt</sub> in PAH-PASMCs is associated with enhanced phosphorylation (p) of CREB (cAMP response element-binding protein), STAT3 (signal transducer and activator of transcription 3), and AKT, increased NFAT (nuclear factor of activated T-cell) nuclear translocation, and elevated level of Ki67 (a marker of cell proliferation).
The findings suggest that cystamine slows but not reverses monocrotaline-induced PAH in rats, which was largely associated with the inhibition of TG2 protein expression and Akt and ERK activation.
Diminished AKT and p70S6 kinase phosphorylation, with increased atrogin-1 and muscle RING-finger protein-1 transcript levels, were evident in the PAH muscle, suggesting engagement of cellular signaling networks stimulating ubiquitin-proteasome-mediated proteolysis of muscle, with concurrent depression of networks mediating muscle hypertrophy.