Involvement of Orai1 Ca2+ channel in the pathogenesis of pulmonary arterial hypertension. Orai1 as a new potential therapeutic target?

Abstract

The pathobiology of pulmonary arterial hypertension (PAH) involves pulmonary arterial smooth muscle cells (PASMCs) dysfunction leading to abnormal proliferation, apoptosis resistance and vasoconstriction. Store-operated Ca 2+ entry (SOCE) strongly contributes to Ca 2+ homeostasis in PASMCs, however, the role of SOCE archetype Orai1 Ca 2+ channel in PAH pathogenesis was unclear. To understand the role of Orai1, we used a combination of Ca 2+ imaging, molecular biology, in vitro, ex vivo and in vivo approaches. We also analyzed the consequence of in vivo pharmacological inhibition of Orai1 in two experimental PH models. We demonstrated that SOCE is increased in human PASMCs from patients with idiopathic PAH (iPAH). Pharmacological inhibition of Orai1 or Orai1 knockdown by siRNA reduced SOCE as well as aberrant proliferation, apoptosis resistance phenotype, exacerbated cell migration and exacerbated calcineurin activity in iPAH-PASMCs. We showed that pharmacological inhibition of Orai1 reduced the capacity of isolated human pulmonary arteries to constrict. In PH rat models induced by Monocrotaline (MCT) or Chronic-Hypoxia (CH) exposure, we found an overexpression of Orai1 in lung and isolated pulmonary arteries. Finally, we found that the in vivo pharmacological inhibition of Orai1 by three different blockers reduced experimental-PH (MCT and CH). Altogether our results provide proof of concept that Orai1 should be considered as a new therapeutic target in PAH.