Editorial

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Open AccessEditorial

Role of Ion Channels in the Development of Pulmonary Arterial Hypertension

by Fabrice Antigny

Biomolecules 2022, 12(10), 1373; https://doi.org/10.3390/biom12101373 - 25 Sep 2022

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Abstract

Pulmonary arterial hypertension (PAH) is an uncommon, progressive, and fatal disease [...] Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

Research

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17 pages, 2783 KiB

Open AccessArticle

Kv7 Channels in Cyclic-Nucleotide Dependent Relaxation of Rat Intra-Pulmonary Artery

by Mohammed Al-Chawishly, Oliver Loveland and Alison M. Gurney

Biomolecules 2022, 12(3), 429; https://doi.org/10.3390/biom12030429 - 10 Mar 2022

Cited by 3 | Viewed by 2206

Abstract

Pulmonary hypertension is treated with drugs that stimulate cGMP or cAMP signalling. Both nucleotides can activate Kv7 channels, leading to smooth muscle hyperpolarisation, reduced Ca²⁺ influx and relaxation. Kv7 activation by cGMP contributes to the pulmonary vasodilator action of nitric oxide, but [...] Read more.

Pulmonary hypertension is treated with drugs that stimulate cGMP or cAMP signalling. Both nucleotides can activate Kv7 channels, leading to smooth muscle hyperpolarisation, reduced Ca²⁺ influx and relaxation. Kv7 activation by cGMP contributes to the pulmonary vasodilator action of nitric oxide, but its contribution when dilation is evoked by the atrial natriuretic peptide (ANP) sensitive guanylate cyclase, or cAMP, is unknown. Small vessel myography was used to investigate the ability of Kv7 channel blockers to interfere with pulmonary artery relaxation when cyclic nucleotide pathways were stimulated in different ways. The pan-Kv7 blockers, linopirdine and XE991, caused substantial inhibition of relaxation evoked by NO donors and ANP, as well as endothelium-dependent dilators, the guanylate cyclase stimulator, riociguat, and the phosphodiesterase-5 inhibitor, sildenafil. Maximum relaxation was reduced without a change in sensitivity. The blockers had relatively little effect on cAMP-mediated relaxation evoked by forskolin, isoprenaline or treprostinil. The Kv7.1-selective blocker, HMR1556, had no effect on cGMP or cAMP-dependent relaxation. Western blot analysis demonstrated the presence of Kv7.1 and Kv7.4 proteins, while selective activators of Kv7.1 and Kv7.4 homomeric channels, but not Kv7.5, caused pulmonary artery relaxation. It is concluded that Kv7.4 channels contribute to endothelium-dependent dilation and the effects of drugs that act by stimulating cGMP, but not cAMP, signalling. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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14 pages, 2391 KiB

Open AccessFeature PaperArticle

Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K⁺ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency

by Maria Callejo, Daniel Morales-Cano, Gema Mondejar-Parreño, Bianca Barreira, Sergio Esquivel-Ruiz, Miguel Angel Olivencia, Laura Moreno, Angel Cogolludo and Francisco Perez-Vizcaino

Biomolecules 2021, 11(6), 795; https://doi.org/10.3390/biom11060795 - 26 May 2021

Cited by 8 | Viewed by 2522

Abstract

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD [...] Read more.

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O₂) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K⁺ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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Review

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21 pages, 1343 KiB

Open AccessReview

Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension

by Gabriel Redel-Traub, Kevin J. Sampson, Robert S. Kass and Michael S. Bohnen

Biomolecules 2022, 12(10), 1341; https://doi.org/10.3390/biom12101341 - 22 Sep 2022

Cited by 6 | Viewed by 2545

Abstract

Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in [...] Read more.

Pulmonary arterial hypertension (PAH) is a devastating disease with high morbidity and mortality. Deleterious remodeling in the pulmonary arterial system leads to irreversible arterial constriction and elevated pulmonary arterial pressures, right heart failure, and eventually death. The difficulty in treating PAH stems in part from the complex nature of disease pathogenesis, with several signaling compounds known to be involved (e.g., endothelin-1, prostacyclins) which are indeed targets of PAH therapy. Over the last decade, potassium channelopathies were established as novel causes of PAH. More specifically, loss-of-function mutations in the KCNK3 gene that encodes the two-pore-domain potassium channel KCNK3 (or TASK-1) and loss-of-function mutations in the ABCC8 gene that encodes a key subunit, SUR1, of the ATP-sensitive potassium channel (KATP) were established as the first two potassium channelopathies in human cohorts with pulmonary arterial hypertension. Moreover, voltage-gated potassium channels (Kv) represent a third family of potassium channels with genetic changes observed in association with PAH. While other ion channel genes have since been reported in association with PAH, this review focuses on KCNK3, KATP, and Kv potassium channels as promising therapeutic targets in PAH, with recent experimental pharmacologic discoveries significantly advancing the field. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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30 pages, 2036 KiB

Open AccessEditor’s ChoiceReview

Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension

by Joana Santos-Gomes, Hélène Le Ribeuz, Carmen Brás-Silva, Fabrice Antigny and Rui Adão

Biomolecules 2022, 12(4), 484; https://doi.org/10.3390/biom12040484 - 22 Mar 2022

Cited by 12 | Viewed by 3465

Abstract

Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase [...] Read more.

Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K⁺, Ca²⁺, Na⁺, and Cl⁻ channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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11 pages, 1117 KiB

Open AccessReview

Channelopathy Genes in Pulmonary Arterial Hypertension

by Carrie L. Welch and Wendy K. Chung

Biomolecules 2022, 12(2), 265; https://doi.org/10.3390/biom12020265 - 07 Feb 2022

Cited by 5 | Viewed by 2657

Abstract

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in [...] Read more.

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The underlying pathogenetic mechanisms are heterogeneous and current therapies aim to decrease pulmonary vascular resistance but no curative treatments are available. Causal genetic variants can be identified in ~13% of adults and 43% of children with PAH. Knowledge of genetic diagnoses can inform clinical management of PAH, including multimodal medical treatment, surgical intervention and transplantation decisions, and screening for associated conditions, as well as risk stratification for family members. Roles for rare variants in three channelopathy genes—ABCC8, ATP13A3, and KCNK3—have been validated in multiple PAH cohorts, and in aggregate explain ~2.7% of PAH cases. Complete or partial loss of function has been demonstrated for PAH-associated variants in ABCC8 and KCNK3. Channels can be excellent targets for drugs, and knowledge of mechanisms for channel mutations may provide an opportunity for the development of PAH biomarkers and novel therapeutics for patients with hereditary PAH but also potentially more broadly for all patients with PAH. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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25 pages, 2446 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Bastien Masson, David Montani, Marc Humbert, Véronique Capuano and Fabrice Antigny

Biomolecules 2021, 11(12), 1781; https://doi.org/10.3390/biom11121781 - 27 Nov 2021

Cited by 13 | Viewed by 2979

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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15 pages, 1541 KiB

Open AccessEditor’s ChoiceReview

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation

by Divya Guntur, Horst Olschewski, Péter Enyedi, Réka Csáki, Andrea Olschewski and Chandran Nagaraj

Biomolecules 2021, 11(11), 1629; https://doi.org/10.3390/biom11111629 - 03 Nov 2021

Cited by 7 | Viewed by 3097

Abstract

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) [...] Read more.

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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25 pages, 2696 KiB

Open AccessReview

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

by Solène Barbeau, Guillaume Gilbert, Guillaume Cardouat, Isabelle Baudrimont, Véronique Freund-Michel, Christelle Guibert, Roger Marthan, Pierre Vacher, Jean-François Quignard and Thomas Ducret

Biomolecules 2021, 11(9), 1389; https://doi.org/10.3390/biom11091389 - 21 Sep 2021

Cited by 17 | Viewed by 3897

Abstract

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular [...] Read more.

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca²⁺]_i) which results from an influx of extracellular Ca²⁺ and/or a release of intracellular stored Ca²⁺. Calcium entry from the extracellular space is a major step in the elevation of [Ca²⁺]_i, involving a variety of plasmalemmal Ca²⁺ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca²⁺-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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