Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension

Redel‐Traub, Gabriel; Sampson, Kevin J.; Kass, Robert S.; Bohnen, Michael S.

doi:10.3390/biom12101341

Cited by 9 publications

(5 citation statements)

References 113 publications

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“…The rs1275988, a CpGSNP meQTL, is located proximal to the promoter of the KCNK3 gene, a well-known causal gene for pulmonary arterial hypertension. 49–51,55 KCNK3 is also highly expressed in the adrenal gland and associated with aldosterone regulation. 56 Interestingly, according to annotations from Roadmap Epigenomics in VannoPortal, 57,58 this locus functions as an enhancer in the aorta, lung, and kidney tissues while remaining inactive in other tissues, including blood and endothelial cells (Figure S9A).…”

Section: Resultsmentioning

confidence: 99%

“…6,48 The locus is situated upstream of a classical promoter CGI for the pulmonary arterial hypertension protective gene KCNK3. [49][50][51] The potential vascular-specific regulation and close connection with DNA methylation motivate us to further investigate the underlying functional mechanisms.…”

Section: Leveraging Dynamics Of Dna Hydroxymethylation and Methylatio...mentioning

confidence: 99%

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Genome-Wide Methylation Analysis Reveals a KCNK3 -Prominent Causal Cascade on Hypertension

Huang,

Shang,

et al. 2024

Circulation Research

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BACKGROUND: Despite advances in understanding hypertension’s genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease’s genetic mechanisms. METHODS: We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988 T/C mutant mice using CRISPR/Cas9, bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the Kcnk3 gene methylation highlighted the mutation’s role in hypertension. RESULTS: We discovered that DNA methylation–associated genetic effects, especially in non-CpG island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type–specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in Kcnk3 gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988 C/C genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the Kcnk3 gene by attenuating Nr2f2 binding at the enhancer locus. CONCLUSIONS: Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation’s potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension’s molecular mechanisms and encourages personalized health care strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Leveraging Dynamics Of Dna Hydroxymethylation and Methylatio...mentioning

confidence: 99%

Genome-Wide Methylation Analysis Reveals a KCNK3 -Prominent Causal Cascade on Hypertension

Huang,

Shang,

et al. 2024

Circulation Research

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“…Loss or reduction of expression and function of potassium channels has been shown to be involved in the pathobiology of PAH, and restoration of these channels ameliorated or reversed PAH in experimental models [ 58 , 59 ]. To date, genetic changes in three families of potassium channels have been observed in association with PAH: the KCNK3 gene that encodes the channel KCNK3 (or TASK-1) that belongs to the two-pore-domain potassium channels (K2P); the ABCC8 gene that encodes the subunit SUR1 of the ATP-sensitive potassium channel (KATP) that corresponds to the inwardly-rectifying potassium channels (Kir); and the voltage-gated potassium channels (Kv) [ 60 , 61 , 62 ]. Heterozygous loss-of-function mutations in KCNK3 were identified in different families of patients with heritable PAH and in patients with idiopathic PAH by whole exome sequencing [ 63 ].…”

Section: Pathobiology Of Pahmentioning

confidence: 99%

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

Miguel

Cruz‐Utrilla

Oliver

et al. 2023

IJMS

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Pulmonary arterial hypertension (PAH) is a severe condition with a high mortality rate despite advances in diagnostic and therapeutic strategies. In recent years, significant scientific progress has been made in the understanding of the underlying pathobiological mechanisms. Since current available treatments mainly target pulmonary vasodilation, but lack an effect on the pathological changes that develop in the pulmonary vasculature, there is need to develop novel therapeutic compounds aimed at antagonizing the pulmonary vascular remodeling. This review presents the main molecular mechanisms involved in the pathobiology of PAH, discusses the new molecular compounds currently being developed for the medical treatment of PAH and assesses their potential future role in the therapeutic algorithms of PAH.

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“…While the mechanism by which changes in O2 tension affect potassium channel activity has not been established, pharmacological modulation of potassium channels may be considered as a therapy to treat conditions associated with hypoxia (Bardou, Trinh, and Brochiero 2009). Since potassium channels regulate the membrane potential of smooth muscle cells, and thus the cytoplasmic free Ca 2+ concentration (Jackson 2005), abnormal function of potassium channels has been linked to pulmonary hypertension (Redel-Traub et al 2022). Potassium channels affect the actin cytoskeleton of developing trachealis smooth muscle via the AKT signaling pathway (Yin et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling regulates ion channel expression to promote smooth muscle and cartilage formation in developing mouse trachea

Russell

Burra

Shah

et al. 2023

Preprint

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Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in non-contractile tissue and embryonic development is less understood. Tracheobronchomalacia (TBM) and complete tracheal rings (CTR) are disorders affecting the muscle and cartilage of the trachea and bronchi, whose etiology remains poorly understood. We demonstrated that trachealis muscle organization and polarity are disrupted after the deletion of Wls, an essential component of the Wnt signaling pathway, in the tracheal epithelium during embryonic development. The changes are similar to the anomalous trachealis muscle observed after the deletion of ion channel genes in developing mouse trachea. We hypothesize that Wnt signaling influences the expression of ion channels to promote trachealis muscle cell assembly and patterning. Deleting Wls in developing trachea causes differential regulation of genes mediating actin binding, cytoskeleton organization, and potassium ion channel activity. Wnt/β-catenin dependent signaling regulated expression of Kcnj13, Kcnd3, Kcnj8, and its related receptor, Abcc9, as demonstrated by in vitro studies and in vivo analysis in Wnt5a and β-catenin deficient tracheas. Pharmacological inhibition of potassium ion channels and Wnt signaling impaired contractility of developing trachealis smooth muscle and formation of cartilaginous mesenchymal condensation. Thus, epithelial-induced Wnt/β-catenin signaling mediates trachealis muscle and cartilage development via modulation of ion channel expression to promote trachealis muscle architecture, contractility, and cartilaginous extracellular matrix in mouse trachea. Ion channel activity may influence tracheal morphogenesis underlying TBM and CTR.

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Potassium Channels as Therapeutic Targets in Pulmonary Arterial Hypertension

Cited by 9 publications

References 113 publications

Genome-Wide Methylation Analysis Reveals a KCNK3 -Prominent Causal Cascade on Hypertension

Genome-Wide Methylation Analysis Reveals a KCNK3 -Prominent Causal Cascade on Hypertension

Novel Molecular Mechanisms Involved in the Medical Treatment of Pulmonary Arterial Hypertension

Wnt signaling regulates ion channel expression to promote smooth muscle and cartilage formation in developing mouse trachea

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