Abstract
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH.
Highlights
Faculté de Médecine, School of Medicine, Université Paris-Saclay, 94276 Le Kremlin-Bicêtre, France; INSERM UMR_S 999 Pulmonary Hypertension: Pathophysiology and Novel Therapies, Groupe Hospitalier
Using a siRNA strategy, they found that the knockdown of STIM2 reduces store-operated Ca2+ entry (SOCE) and proliferation of idiopathic PAH (iPAH) hPASMC without any effect on control hPASMC [136]. They demonstrated that the transition of rat pulmonary arterial smooth muscle cell (PASMC) from a contractile to proliferative phenotype was associated with enhanced SOCE due to increased expression of Orai2, STIM2, and TRPC6 [135]
The recent advance in the determination of cryo-EM structures of transient receptor potential2+canonical channels nels (TRPCs) channels with sufficient resolution to allow the identification of specific bounding site of small molecules [251,252] should help to develop more potent selective inhibitors or activators, since the need of selective molecules is crucial for the development of innovative therapy in various diseases, including Pulmonary arterial hypertension (PAH)
Summary
The modulation of intracellular Ca2+ concentration ([Ca2+ ]i ) constitutes a signal transduction mechanism for all cell types, regulating a large range of cellular functions, including contraction, proliferation, migration, gene transcription, metabolism, death, and apoptosis [1,2,3]. Ca channels (SOCs), which produce store-operated Ca2+ entry (SOCE). The advent of molecular biology techniques has made it possible to identify the molecules responsible for SOCE. In several cell types, in addition to Orai Ca2+. In several cell types, in addition to Orai Ca channel activation, STIM molecules activate transient receptor potential canonical chanchannel activation, STIM molecules activate transient receptor potential2+canonical channels nels (TRPCs), which are nonselective cation channels permeable to. 2+]ER) [11,12,13,14] (Figure 1) This EF hand domain forms with the sterile alpha motif (SAM). This EF hand domain forms with the sterile alpha motif (SAM) of the EF–SAM of the EF–SAM which oligomerizes after ER [12,15,16].
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