scholarly journals Altered expression and signal transduction of endothelin-1 receptors in heritable and idiopathic pulmonary arterial hypertension

2012 ◽  
Vol 228 (2) ◽  
pp. 322-329 ◽  
Author(s):  
Jun Yu ◽  
Linda Taylor ◽  
Jamie Wilson ◽  
Suzy Comhair ◽  
Serpil Erzurum ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Altered Expression ◽  
Endothelin 1 ◽  
Pulmonary Arterial

Abstract 2301: Agonistic Autoantibodies Against the Endothelin 1 ETA - and α1-Adrenergic- Receptor in the Sera of Patients with Idiopathic Pulmonary Arterial Hypertension.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Gerd Wallukat ◽  
Michael Dandel ◽  
Johannes Müller ◽  
Sabine Bartel ◽  
Wolfgang Schulze ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Chronotropic Effect ◽  
Rat Cardiomyocytes ◽  
Endothelin 1 ◽  
Signal Cascade ◽  
Eta Receptor ◽  
Pulmonary Arterial ◽  
Agonistic Effect

Background: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive fatal disease of unknown cause. This disease is accompanied by an massive increase of pulmonary vascular resistance (remodelling and increase of vascular tonus) inducing right heart failure. It was shown that the synthesis of vasoconstrictors (endothelin 1, thromboxane A2, serotonine) is elevated in patients with IPAH. Methods: We analyzed sera of patients with PH with regards to functional autoantibodies (AABs) against G-protein coupled receptors using spontaneously beating rat cardiomyocytes as bioassay. Moreover, we investigated the effect of the AAB on the translocation of the transcription factors NFκB and AP-1. Results: The sera of patients with IPAH contain functional AABs against the α1-adrenergic (α1-AR) and the endothelin1 ETA receptor. We purified the AABs by affinity chromatography. AABs against the α1-AR exert a positive chronotropic effect. AABs against the ETA receptor induce like endothelin 1 a negative chronotropic effect. The agonistic effect of the AABs was dose-dependent and blocked by prazosine (α1-AR blocker) and BQ610 (ETA antagonist), respectively. Moreover, the agonistic effect of the AABs was neutralized by peptides corresponding to the second extracellular loop of both receptors. Therefore, the epitopes of the AABs are localized on the second extracellular loops of the receptors. The α1-AR AABs as well as the ETA-receptor AABs induce a permanent stimulation without desensitization of the receptor mediated signal cascade. The α1-adrenergic agonist phenylephrine and endothelin1 as ET receptor agonist cause a translocation of the transcription factor NFκB and AP-1 from the cytosol into the nucleus in cultured neonatal rat cardiomyocytes. The same translocation was observed using the AABs against the α1-AR and ETA receptor. Conclusion: The agonist-like AABs against the α1-AR and the ETA receptor influence in vitro the signalling of cultured cells. Moreover, the AABs prevent the desensitization of the receptor mediated signal cascade normally seen by ongoing receptor stimulation. Therefore, we assumed that the functional AABs against the α1-AR and the ETA receptor may be involved in the pathogenesis of IPAH.

Function of Kv1.5 channels and genetic variations ofKCNA5in patients with idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 292 (5) ◽  
pp. C1837-C1853 ◽  
Author(s):  
Carmelle V. Remillard ◽  
Donna D. Tigno ◽  
Oleksandr Platoshyn ◽  
Elyssa D. Burg ◽  
Elena E. Brevnova ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Single Channel ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Inactivation Kinetics ◽  
Nucleotide Polymorphisms ◽  
Coding Region ◽  
Α Subunit ◽  
Altered Expression ◽  
Pulmonary Arterial

The pore-forming α-subunit, Kv1.5, forms functional voltage-gated K+(Kv) channels in human pulmonary artery smooth muscle cells (PASMC) and plays an important role in regulating membrane potential, vascular tone, and PASMC proliferation and apoptosis. Inhibited Kv channel expression and function have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). Here, we report that overexpression of the Kv1.5 channel gene ( KCNA5) in human PASMC and other cell lines produced a 15-pS single channel current and a large whole cell current that was sensitive to 4-aminopyridine. Extracellular application of nicotine, bepridil, correolide, and endothelin-1 (ET-1) all significantly and reversibly reduced the Kv1.5 currents, while nicotine and bepridil also accelerated the inactivation kinetics of the currents. Furthermore, we sequenced KCNA5 from IPAH patients and identified 17 single-nucleotide polymorphisms (SNPs); 7 are novel SNPs. There are 12 SNPs in the upstream 5′ region, 2 of which may alter transcription factor binding sites in the promoter, 2 nonsynonymous SNPs in the coding region, 2 SNPs in the 3′-untranslated region, and 1 SNP in the 3′-flanking region. Two SNPs may correlate with the nitric oxide-mediated decrease in pulmonary arterial pressure. Allele frequency of two other SNPs in patients with a history of fenfluramine and phentermine use was significantly different from patients who have never taken the anorexigens. These results suggest that 1) Kv1.5 channels are modulated by various agonists (e.g., nicotine and ET-1); 2) novel SNPs in KCNA5 are present in IPAH patients; and 3) SNPs in the promoter and translated regions of KCNA5 may underlie the altered expression and/or function of Kv1.5 channels in PASMC from IPAH patients.

Endothelin-1 gen (EDN1) regulating miRNAs are downregulated in Idiopathic Pulmonary Arterial Hypertension

2020 ◽  
Author(s):  
Adolfo Baloira Villar ◽  
Mauro Lago Docampo ◽  
Carlos López ◽  
Carlos Vilariño ◽  
Joan Albert Barberá ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Endothelin 1 ◽  
Pulmonary Arterial
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