endothelin-1 and Pulmonary-Arterial-Hypertension

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

Topics: Channelopathies; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; KATP Channels; Nerve Tissue Proteins; Potassium; Potassium Channels, Tandem Pore Domain; Potassium Channels, Voltage-Gated; Prostaglandins I; Pulmonary Arterial Hypertension

To study the association between hepatocyte growth factor (HGF) and treatment response in mice with hypoxic pulmonary arterial hypertension (HPAH) and the possibility of HGF as a new targeted drug for HPAH.. After successful modeling, the HPAH model mice were randomly divided into two groups: HPAH group and HGF treatment group (tail vein injection of recombinant mouse HGF 1 mg/kg), with 10 mice in each group. Ten normal mice were used as the control group. After 5 weeks, echocardiography was used to measure tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio; the Griess method was used to measure the content of nitric oxide in serum; ELISA was used to measure the serum level of endothelin-1; transmission electron microscopy was used to observe changes in the ultrastructure of pulmonary artery.. Compared with the HGF treatment and normal control groups, the HPAH group had significantly higher tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio (. Increasing serum HGF level can alleviate the impact of HPAH on the cardiovascular system of mice, possibly by repairing endothelial cell injury, improving vascular remodeling, and restoring the normal vasomotor function of pulmonary vessels.

Topics: Animals; Body Weight; Endothelial Cells; Endothelin-1; Hepatocyte Growth Factor; Hypertrophy, Right Ventricular; Hypoxia; Mice; Nitric Oxide; Pulmonary Arterial Hypertension

Inflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ET. Serum levels of anti-ET. Anti-ET. This study provides evidence for an anti-inflammatory role of ET

Topics: Animals; Autoantibodies; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertrophy, Right Ventricular; Inflammation; Mice; Pulmonary Arterial Hypertension; Receptor, Endothelin B; Scleroderma, Systemic

Glioma-associated oncogene homolog 1 (GLI1), a zinc-finger transcription factor, is upregulated in tumors and promotes cancer cell proliferation and migration. However, whether GLI1 involves in pulmonary artery smooth muscle cells (PASMCs) proliferation and migration and the detailed molecular mechanisms underlying GLI1 in pulmonary arterial hypertension (PAH) are not yet clear. Primary cultured rat PASMCs and monocrotaline (MCT)-induced PAH rats model were applied to address these issues in the present study. We found that the expression of GLI1 was significantly increased in endothelin-1 (ET-1) treated PASMCs, accompanied with the activation of microRNA (miR)-27b-3p/F-box and WD repeat domain containing 7 (FBXW7)/kruppel-like factor 5 (KLF5)/GLI1 pathway through endothelin-1 receptor type A (ETAR). Elevated miR-27b-3p suppressed FBXW7 expression, which led to KLF5 accumulation by decreasing its ubiquitinated degradation, KLF5 further induced GLI1 upregulation leading to PASMCs proliferation and migration. In addition, in MCT-induced PAH rats, targeting ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway effectively prevented the pulmonary vascular remodeling and the development of PAH in rats. Our study indicates that interfering ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 signaling axis might have a potential value in the prevention and treatment of PAH.

Topics: Animals; Cell Proliferation; Endothelin-1; F-Box-WD Repeat-Containing Protein 7; Kruppel-Like Transcription Factors; MicroRNAs; Monocrotaline; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats; Receptor, Endothelin A; Zinc Finger Protein GLI1

Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during PAH development. Previous studies showed that miR-486 could reduce apoptosis in different cells; however, the role of miR-486 in PAH development or HPASMC proliferation and migration remains unclear. After 6 h of hypoxia treatment, miR-486-5p was significantly upregulated in HPASMCs. We found that miR-486-5p could upregulate the expression and secretion of ET-1. Furthermore, transfection with a miR-486-5p mimic could induce HPASMC proliferation and migration. We also found that miRNA-486-5p could downregulate the expression of SMAD2 and the phosphorylation of SMAD3. According to previous studies, the loss of SMAD3 may play an important role in miRNA-486-5p-induced HPASMC proliferation. Although the role of miRNA-486-5p in PAH in in vivo models still requires further investigation and confirmation, our findings show the potential roles and effects of miR-486-5p during PAH development.

Topics: Cell Movement; Cell Proliferation; Cells, Cultured; Endothelin-1; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; MicroRNAs; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery

Atrial arrhythmias are considered prominent phenomena in pulmonary arterial hypertension (PAH) resulting from atrial electrical and structural remodeling. Endothelin (ET)-1 levels correlate with PAH severity and are associated with atrial remodeling and arrhythmia. In this study, hemodynamic measurement, western blot analysis, and histopathology were performed in the control and monocrotaline (MCT, 60 mg/kg)-induced PAH rabbits. Conventional microelectrodes were used to simultaneously record the electrical activity in the isolated sinoatrial node (SAN) and right atrium (RA) tissue preparations before and after ET-1 (10 nM) or BQ-485 (an ET-A receptor antagonist, 100 nM) perfusion. MCT-treated rabbits showed an increased relative wall thickness in the pulmonary arterioles, mean cell width, cross-sectional area of RV myocytes, and higher right ventricular systolic pressure, which were deemed to have PAH. Compared to the control, the spontaneous beating rate of SAN-RA preparations was faster in the MCT-induced PAH group, which can be slowed down by ET-1. MCT-induced PAH rabbits had a higher incidence of sinoatrial conduction blocks, and ET-1 can induce atrial premature beats or short runs of intra-atrial reentrant tachycardia. BQ 485 administration can mitigate ET-1-induced RA arrhythmogenesis in MCT-induced PAH. The RA specimens from MCT-induced PAH rabbits had a smaller connexin 43 and larger ROCK1 and phosphorylated Akt than the control, and similar PKG and Akt to the control. In conclusion, ET-1 acts as a trigger factor to interact with the arrhythmogenic substrate to initiate and maintain atrial arrhythmias in PAH. ET-1/ET-A receptor/ROCK signaling may be a target for therapeutic interventions to treat PAH-induced atrial arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Connexin 43; Disease Models, Animal; Endothelin-1; Familial Primary Pulmonary Hypertension; Monocrotaline; Proto-Oncogene Proteins c-akt; Pulmonary Arterial Hypertension; Pulmonary Artery; Rabbits

Pulmonary hypertension (PH) causes cardiac hypertrophy in the right ventricle (RV) and eventually leads to RV failure due to persistently elevated ventricular afterload. We hypothesized that the mechanical stress on the RV associated with increased afterload impairs vasodilator function of the right coronary artery (RCA) in PH. Coronary vascular response was assessed using microangiography with synchrotron radiation (SR) in two well-established PH rat models, monocrotaline injection or the combined exposure to chronic hypoxia and vascular endothelial growth factor receptor blockade with Su5416 (SuHx model). In the SuHx model, the effect of the treatment with the nonselective endothelin-1 receptor antagonist (ERA), macitentan, was also examined. Myocardial viability was determined in SuHx model rats, using

Topics: Animals; Antihypertensive Agents; Coronary Angiography; Coronary Vessels; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hypertrophy, Right Ventricular; Hypoxia; Indoles; Monocrotaline; Predictive Value of Tests; Pulmonary Arterial Hypertension; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Severity of Illness Index; Sulfonamides; Synchrotrons; Vasodilation; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.

Topics: Case-Control Studies; Cell Proliferation; Cells, Cultured; Collagen; Elastin; Endothelin-1; Epoprostenol; Gene Expression Profiling; Humans; Lung; Lung Transplantation; Myocytes, Smooth Muscle; Pneumonectomy; Primary Cell Culture; Protein-Lysine 6-Oxidase; Pulmonary Arterial Hypertension; Pulmonary Artery; Trapidil; Up-Regulation

Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.

Topics: Administration, Intravenous; Animals; Cation Transport Proteins; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin-1; Gene Knock-In Techniques; Hepcidins; Humans; Iron; Iron Deficiencies; Male; Mice; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Receptor, Endothelin A; Up-Regulation