Mutual Inhibitory Mechanisms between PPAR? and Hif-1?: Implication in Pulmonary Hypertension

Abstract

Transcription factor hypoxia-inducible factor 1? (Hif-1?) is known for its crucial role in promoting the pathogenesis of pulmonary hypertension (PH). Previous studies have indicated the in-depth mechanisms that Hif-1? 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 ? (PPAR?) 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-1?. These results provided convincing evidence and novel mechanisms in supporting the protective roles of PPAR? 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 PPAR? and Hif-1?. Basically, under chronic hypoxic stress, accumulated Hif-1? leads to abolished expression of PPAR? and progressive imbalance between PPAR? and Hif-1?, which promotes the PH progression; however, targeted PPAR? restoration approach reversely inhibits Hif-1? level and Hif-1? mediated signaling transduction, which subsequently attenuates the elevated pulmonary arterial pressure and vascular remodeling under PH pathogenesis.