Transcription factor hypoxia-inducible factor 1α (Hif-1α) is known for its crucial role in promoting the pathogenesis of pulmonary hypertension (PH). Previous studies have indicated the in-depth mechanisms that Hif-1α increases the distal pulmonary arterial (PA) pressure and vascular remodeling by triggering the intracellular calcium homeostasis, especially the store-operated calcium entry (SOCE) process. In our recent research paper published in the Journal of Molecular Medicine, we found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) activation could attenuate the PH pathogenesis by suppressing the elevated distal PA pressure and vascular remodeling. Moreover, these effects are likely mediated through the inhibition of SOCE by suppressing Hif-1α. These results provided convincing evidence and novel mechanisms in supporting the protective roles of PPARγ on PH treatment. Then, by using comprehensive loss-of-function and gain-of-function strategies, we further identified the presence of a mutual inhibitory mechanism between PPARγ and Hif-1α. Basically, under chronic hypoxic stress, accumulated Hif-1α leads to abolished expression of PPARγ and progressive imbalance between PPARγ and Hif-1α, which promotes the PH progression; however, targeted PPARγ restoration approach reversely inhibits Hif-1α level and Hif-1α mediated signaling transduction, which subsequently attenuates the elevated pulmonary arterial pressure and vascular remodeling under PH pathogenesis.
Keywords: Hif-1α; PPARγ; Pulmonary hypertension; SOCE.