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

Our previous publication demonstrated that peroxisome proliferator-activated receptor γ (PPARγ) inhibits the pathogenesis of chronic hypoxia (CH)-induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process of PPARγ on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O2) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1-fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn(2+) quenching and extracellular Ca(2+) restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up-regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARγ agonist, GW1929, we detected that PPARγ activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARγ on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARγ and caveolin-1, and PPARγ antagonist, T0070907, we observed that PPARγ plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARγ inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs.