Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

Masson, Bastien; Montani, David; Humbert, Marc; Capuano, Véronique; Antigny, Fabrice

doi:10.3390/biom11121781

Cited by 14 publications

(18 citation statements)

References 253 publications

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“…TRPC channels are constituted by seven isoforms (TRPC1 to TRPC7, with TRPC2 being a pseudogene in humans), which can form homo- or hetero-tetrameric channels like TRPC1/5, TRPC1/3, TRPC1/4, TRPC3/4, TRPC4/5, and TRPC1/4/5 [ 17 ]. The inhibition of TRPC channels by pharmacological or knockdown approaches indicates that TRPC1, C4, and C5 participate to SOCE in several cell types [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Generality About the Soce Machinerymentioning

confidence: 99%

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

Sabourin

Beauvais

Luo

et al. 2022

Cells

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Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic knowledge of RV remodeling. Since the physiology and hemodynamic function of the RV differ from those of the left ventricle (LV), the mechanisms of LV dysfunction cannot be generalized to that of the RV, albeit a knowledge of these being helpful to understanding RV remodeling and dysfunction. Store-operated Ca2+ entry (SOCE) has recently emerged to participate in the LV cardiomyocyte Ca2+ homeostasis and as a critical player in Ca2+ mishandling in a pathological context. In this paper, we highlight the current knowledge on the SOCE contribution to the LV and RV dysfunctions, as SOCE molecules are present in both compartments. he relative lack of studies on RV dysfunction indicates the necessity of further investigations, a significant challenge over the coming years.

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Section: Generality About the Soce Machinerymentioning

confidence: 99%

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

Sabourin

Beauvais

Luo

et al. 2022

Cells

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“…proliferation and hypertrophy of smooth muscle cells, instigated in particular by signalling cascades with calcium (Masson et al 2021), hypoxia-induced factor (Liu et al 2019), sphingosine-1-phosphate (Ranasinghe et al 2020), etc. Zinc homeostasis is vital for functioning of the immune and other organs and systems. Cellular zinc homeostasis is regulated by three major families of proteins: (1) Solute Carrier 39 family/Zrt-and Irt-like proteins (SLC39A/ ZIPs), which import zinc ions into the cytosolic compartment from the extracellular space or intracellular vesicles;…”

Section: Introductionmentioning

confidence: 99%

Immunolocalization of zinc transporters and metallothioneins reveals links to microvascular morphology and functions

Tran

Jakobczak

Abdo

et al. 2022

Histochem Cell Biol

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Zinc homeostasis is vital to immune and other organ system functions, yet over a quarter of the world’s population is zinc deficient. Abnormal zinc transport or storage protein expression has been linked to diseases, such as cancer and chronic obstructive pulmonary disorder. Although recent studies indicate a role for zinc regulation in vascular functions and diseases, detailed knowledge of the mechanisms involved remains unknown. This study aimed to assess protein expression and localization of zinc transporters of the SLC39A/ZIP family (ZIPs) and metallothioneins (MTs) in human subcutaneous microvessels and to relate them to morphological features and expression of function-related molecules in the microvasculature. Microvessels in paraffin biopsies of subcutaneous adipose tissues from 14 patients undergoing hernia reconstruction surgery were analysed for 9 ZIPs and 3 MT proteins by MQCM (multifluorescence quantitative confocal microscopy). Zinc regulation proteins detected in human microvasculature included ZIP1, ZIP2, ZIP8, ZIP10, ZIP12, ZIP14 and MT1-3, which showed differential localization among endothelial and smooth muscle cells. ZIP1, ZIP2, ZIP12 and MT3 showed significantly (p < 0.05) increased immunoreactivities, in association with increased microvascular muscularization, and upregulated ET-1, α-SMA and the active form of p38 MAPK (Thr180/Tyr182 phosphorylated, p38 MAPK-P). These findings support roles of the zinc regulation system in microvascular physiology and diseases.

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“…6,7 The contribution of Orai1-mediated SOCE to the proliferation and migration of systemic endothelial and vascular smooth muscle cells (SMCs) has been described. 5 Currently, Orai1 is considered as a potential target for several pathological processes, including asthma and psoriasis. 8 However, the role of Orai1 in pulmonary vascular remodeling remains elusive.…”

mentioning

confidence: 99%

“…Cellular calcium (Ca 2+ ) mishandling is a significant cause of PASMC dysfunction in PAH. 4,5 Although the role of Orai1 in nonexcitable cells is well established, the role of Orai1-mediated store-operated Ca 2+ (SOC) entry (SOCE) in excitable cells, such as PASMCs, remains unclear. Two major SOC components have been identified: the STIM (stromal interaction molecule family; STIM1 and STIM2) and the Orai1 Ca 2+ channel (also called Calcium Release-Activated Calcium Channel Protein 1) (CRACM1 [calcium release-activated calcium modulator 1]).…”

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confidence: 99%

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension

Masson

Ribeuz

Sabourin

et al. 2022

Circulation Research

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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.

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Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

Cited by 14 publications

References 253 publications

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

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

Immunolocalization of zinc transporters and metallothioneins reveals links to microvascular morphology and functions

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension

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