Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry

Abstract

In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) on store-operated calcium entry (SOCE) and expression of the main store-operated calcium channels (SOCCs) components, canonical transient receptor potential (TRPC) in chronic hypoxia (CH) and monocrotaline (MCT)-induced PH rat models. siRNA knockdown and adenoviral overexpression strategies were constructed for both loss-of-function and gain-of-function experiments. PPARγ agonist rosiglitazone attenuates the pathogenesis of both CHPH and MCT-PH, suppresses Hif-1α, TRPC1, TRPC6 expression in the distal pulmonary artery (PA) and SOCE in freshly isolated rat distal pulmonary arterial smooth muscle cells (PASMCs). By comprehensive use of knockdown and overexpression studies, bioinformatically analysis of the TRPC gene promoter and luciferase reporter assay, we demonstrated that PPARγ exerts roles of anti-proliferation, anti-migration, and pro-apoptosis in PASMCs, likely by inhibiting the elevated SOCE and TRPC expression. These effects were inhibited under the conditions of hypoxia or Hif-1α accumulation. We also found that under hypoxia, accumulated Hif-1α protein acts as upstream of suppressed PPARγ level, however, targeted PPARγ rescue acts negative feedback on suppressing Hif-1α level and Hif-1α mediated signaling pathway. PPARγ inhibits PH by targeting SOCE and TRPC via inhibiting Hif-1α expression and signaling transduction.

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

“…Our previous studies and those of others have demonstrated the protective roles of PPARg ligands on CHPH disease progression (12,13). These beneficial roles are likely mediated through inhibiting SOCE and the expression of SOCCs channel protein TRPCs, which then lead to suppressed proliferation and migration of PASMCs (11,13).…”

“…These beneficial roles are likely mediated through inhibiting SOCE and the expression of SOCCs channel protein TRPCs, which then lead to suppressed proliferation and migration of PASMCs (11,13). Previous studies have reported that, in cancer cell lines, caveolin-1 acts as a direct transcription target of the main hypoxic regulator, hypoxia-inducible factors 1 and 2, and facilitates the proproliferative consequences during the process of tumorigenesis (47,48).…”

“…Peroxisome proliferator-activated receptor (PPAR) g belongs to a kind of ligand-activated nuclear hormone receptor superfamily, which is ubiquitously expressed in pulmonary vascular endothelial and smooth muscle cells, and acts as a transcription factor to modulate the transcription of a number of genes (8). Previous studies reported that PPARg is down-regulated in the lungs (9,10) and distal PAs (11) of experimental PH models, whereas restoration of PPARg by specific agonists can markedly attenuate the PH pathogenesis by normalizing the elevated right ventricle systolic pressure and distal PA remodeling (12)(13)(14). Moreover, we further demonstrated the molecular mechanisms that PPARg inhibits PA remodeling and PASMC proliferation, mainly by targeting SOCE and TRPC proteins (11,13).…”

Orai channel-mediated Ca2+signals in vascular and airway smooth muscle

“…They proposed that PPAR␥ decreases proliferation and migration of pulmonary artery SMCs through inhibition of SOCE, which is upregulated by exposure to hypoxia. In the same study, they correlated their findings with expression of TRPC1 and TRPC6 proteins; however, STIM/Orai isoform expression was not addressed (97). In a subsequent study, Yang et al (100) suggested that enhanced SOCE in hypoxia-exposed pulmonary artery SMCs is mediated through the upregulation of caveolin-1, arguing that SOCE channels are organized within caveolin-rich regions.…”

“…Ng et al (58) subsequently proposed that interactions between TRPC1, Orai1, and STIM1 underlie SOCE induced by acute hypoxia in pulmonary artery SMCs. Wang et al (97) proposed that peroxisome proliferator-activated receptor-␥ (PPAR␥) plays a protective role in pulmonary hypertension induced by chronic hypoxia. They proposed that PPAR␥ decreases proliferation and migration of pulmonary artery SMCs through inhibition of SOCE, which is upregulated by exposure to hypoxia.…”