Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca 2+ ) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca 2+ entry is involved in Ca 2+ homeostasis in PASMCs, but its properties in PAH are unclear. Methods: Using a combination of Ca 2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH). Results: Store-operated Ca 2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2, NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using siRNA and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca 2+ entry, mitochondrial Ca 2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (BTP2, JPIII, or 5J4) protected against PH. Conclusions: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology

“…That is why the arsenal of pharmacological Orai1 inhibitors has significantly increased over the last decade. Indeed, there is a well-described family of pyrazole derivatives, with the commonly used BTP2 (N-{4-[3,5-bis(Trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide or YM-58483) [ 122 , 123 , 124 , 125 ] and GSK compounds (GSK7975A and GSK-5503A) [ 126 ], the BTP2-derivative Synta-66, which binds directly Orai1 [ 127 , 128 , 129 ] and its suitable in vivo and more selective analog JPIII that we have developed [ 72 , 130 ]. The less-used AnCoA4 [ 131 ] and 5J4 (N-[[(6-Hydroxy-1-naphthalenyl)amino]thioxomethyl]-2-furancarboxamide) [ 132 ] also exist.…”

“…We have demonstrated that Orai1 function contributes to human pulmonary arterial hypertension (PAH) and to several preclinical models of pulmonary hypertension (PH). We have showed that Orai1 inhibition, by BTP2, 5J4, or JPIII, corrects in vitro the aberrant phenotypes of human pulmonary artery smooth muscles cells and attenuates in vivo PH in rat models, suggesting that Orai1 inhibition should be considered a relevant therapy in PAH [ 130 ]. We have also demonstrated that, after chronic pressure overload, JPIII markedly improves the left ventricular systolic function and Ca 2+ handling by preventing the Ca 2+ cycling mishandling, SERCA2a downregulation and fibrosis, without causing adverse effect.…”

Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension

“…Pulmonary vascular remodeling was assessed in all the pulmonary vessels larger than 50 μm and less than 100 μm identified in 20 randomly selected microscopic fields per tissue section. The wall thickness was calculated according to the following equation: [External diameter–Internal diameter)/(External diameter)] × 100, as previously described ( 19 ).…”

MonOrail to Cure? Targeting Orai1 to Reverse Pulmonary Arterial Hypertension

“…In conclusion, the article by Masson et al 11 provides important information about the role and translational significance of Orai1 in PASMC remodeling in PAH and opens several important avenues for further investigation to expand our understanding of the role of Orai channels beyond PASMCs and to further explore the potential attractiveness of targeting Orai1 to treat this devastating disease.…”

“…10,11,13 Further expanding our knowledge, Masson et al report that Orai1 over-accumulation in PASMCs from patients with advanced PAH is supported by proproliferative-prosurvival MEK1/2, pro-inflammatory NFAT and NFkB, and by a deficiency of antiproliferative KCNK3 independently of BMPR2 and Akt/mTOR. 11 Continuing to unravel Orai1-dependent signaling, the authors show that Orai1 supports the pro-proliferative/pro-migratory PAH PASMC phenotype by downregulating cell cycle inhibitor p21, p38 signaling, caspase 9 activity, and through activation of serine/threonine phosphatase calcineurin. This leads us to hypothesize that in PAH PASMCs Orai1 could act as a signaling hub that coordinates growth factor and inflammatory signals to enable cell cycle progression, enhance migratory potential, and protect cells from apoptosis.…”