Potassium (K+) channels in the pulmonary vasculature: Implications in pulmonary hypertension Physiological, pathophysiological and pharmacological regulation

Mondéjar-Parreño, Gema; Cogolludo, Ángel; Pérez‐Vizcaíno, Francisco

doi:10.1016/j.pharmthera.2021.107835

Cited by 24 publications

(17 citation statements)

References 284 publications

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“…K + channels play a fundamental role in controlling PASMC membrane potential and pulmonary arterial tone [39]. Ionic channel remodeling due to a decrease in the activity and expression of potassium channels, mainly Kv1.5 and TASK-1, which result in PA vasoconstriction, hypertrophy and proliferation, is considered an early event in the pathobiology of PAH [7,[40][41][42].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Their activation, inducing a cellular hyperpolarization, acts as counterparts to TRPV4 or Piezo1 depolarization activity, enabling fine-tuning of mechanosensation, reducing cellular contraction in response to mechanical forces [ 171 ]. Potassium flux is also involved in cell proliferation and inflammation [ 172 , 173 ].…”

Section: Other Mechanosensitive Channelsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

“…A wide variety of cationic channels are functionally expressed in pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells 4 – 6 . K + channel conductance plays a fundamental role in the control of their membrane potential (Em), which regulates the cell excitability and the activity of other voltage-gated channels including Ca 2+ channels 6 . Ca 2+ conductance in the cell membrane is the main determinant of cytosolic Ca 2+ which in turn regulates the contractility of pulmonary arteries, the release of endothelial factors and neurotransmitters and the cell proliferation/apoptotic balance.…”

Section: Introductionmentioning

confidence: 99%

“…Some of these disorders may be corrected by drugs and therefore, ion channels represent the second largest group of drug targets after G protein-coupled receptors 7 . Alterations in the K + and Ca 2+ channel density and activity at the cell surface strongly impact in the pulmonary circulation 4 – 6 . These diseases may result from a mutation in the encoding genes, from dysregulated gene expression, from the blockade of the ion channel protein by toxins or drugs or from other forms of impaired regulation of channel activity.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic profile of cationic channels in human pulmonary arterial hypertension

Pérez‐Vizcaíno

Cogolludo

Mondéjar-Parreño

2021

Sci Rep

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The dysregulation of K+ channels is a hallmark of pulmonary arterial hypertension (PAH). Herein, the channelome was analyzed in lungs of patients with PAH in a public transcriptomic database. Sixty six (46%) mRNA encoding cationic channels were dysregulated in PAH with most of them downregulated (83%). The principal component analysis indicated that dysregulated cationic channel expression is a signature of the disease. Changes were very similar in idiopathic, connective tissue disease and congenital heart disease associated PAH. This analysis 1) is in agreement with the widely recognized pathophysiological role of TASK1 and KV1.5, 2) supports previous preliminary reports pointing to the dysregulation of several K+ channels including the downregulation of KV1.1, KV1.4, KV1.6, KV7.1, KV7.4, KV9.3 and TWIK2 and the upregulation of KCa1.1 and 3) points to other cationic channels dysregulated such as Kv7.3, TALK2, CaV1 and TRPV4 which might play a pathophysiological role in PAH. The significance of other changes found in Na+ and TRP channels remains to be investigated.

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Potassium (K+) channels in the pulmonary vasculature: Implications in pulmonary hypertension Physiological, pathophysiological and pharmacological regulation

Cited by 24 publications

References 284 publications

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

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

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

Transcriptomic profile of cationic channels in human pulmonary arterial hypertension

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