osteoprotegerin and Hypertension--Pulmonary

Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity.. Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416- and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin α. Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease.

Topics: Animals; Arterial Pressure; Case-Control Studies; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Female; Focal Adhesion Kinase 1; Humans; Hypertension, Pulmonary; Hypoxia; Indoles; Integrin alphaVbeta3; Male; Mice, Knockout; Middle Aged; Monocrotaline; Muscle, Smooth, Vascular; Osteoprotegerin; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Pyrroles; Rats, Sprague-Dawley; RNA Interference; Severity of Illness Index; Signal Transduction; Transfection; Vascular Remodeling; Walk Test

Osteoprotegerin (OPG) may predict progression of chronic congestive heart failure (CHF) with increased mortality and play an important role in the development of pulmonary arterial hypertension (PAH). Mounting evidence suggests that PAH developed during CHF is not solely caused by a "passive" increase from the left ventricular enddiastolic pressure, but rather a "reactive" response from contributing lung endothelial dysfunction and vascular remodelling, a pathological process that can be significantly influenced by endothelial progenitor cells (EPCs).This study aims to examine whether circulating EPCs from patients with CHF are affected and if OPG could be implicated during disease progression.. In this study EPCs were isolated, cultured, and quantified from patients of CHF with (n = 20) or without PAH (n=40) as measured by right heart catheterization. Serum levels of OPG and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were analysed and correlated with EPCs.. A significant decrease in circulating EPCs (39.3 ?9.1 vs 67.1 ?10.5 EPCs/x200 field; P <0.05) was found in CHF patients who developed PAH compared to those without PAH. Both OPG (551.90 +/- 49.83 vs. 312.29 +/- 31.12 pg/ml; P<0.05) and NT-pro BNP (2,946.50 +/- 1,434.50 vs. 1,328.20 +/- 811.90; P < 0.05) were also significantly elevated in CHF patients with PA H. Circulating level of OPG correlated inversely with EPCs (r = -0.45, P = 0.037) but positively with mPAP (r =0.53, P=0.011).. Our study demonstrates that OPG elevation and EPC depletion are associated with CHF patients who have developed PAH. The inverse relationship of circulating OPG with EPCs suggests a possible mechanism for OPG in the development of pulmonary vascular dysfunction, thus worsening prognosis for CHF patients.

Topics: Adult; Cells, Cultured; Disease Progression; Echocardiography, Doppler, Color; Endothelial Progenitor Cells; Endothelium, Vascular; Female; Heart Failure, Systolic; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Prognosis

Inflammation plays a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Soluble receptor activator of nuclear factor-ĸB ligand (sRANKL) and osteoprotegerin (OPG) are tumor necrosis factor α family members of immunomodulatory activity.. The aim of the study was to evaluate sRANKL and OPG concentrations in patients with PAH as potential factors contributing to the development of the disease.. We studied 26 patients with PAH, 31 volunteers, and 24 stable patients with chronic systolic left ventricular heart failure (LVHF) without pulmonary hypertension. The PAH group was followed up for 6 months for clinical deterioration or death.. sRANKL levels were higher in the PAH group compared with controls and the LVHF group (5.6 [interquartile range, 3.9-7.9) vs. 2.0 [0.9-4.4] pmol/l; P = 0.0001, and 2.4 [1.3-4.2] pmol/l; P = 0.001, respectively). OPG levels were higher in PAH patients compared with controls (4.07 ±1.9 vs. 3.27 ±0.95 pmol/l; P = 0.048). We found significant correlations between sRANKL levels and parameters of ventilatory efficiency during exercise in the PAH group. OPG levels correlated with brain natriuretic peptide levels and with invasive hemodynamic parameters. Patients with clinical deterioration during 6-month follow-up (n = 9) showed higher baseline OPG levels compared with stable patients (n = 17, 5.09 ±2.6 vs. 3.52 ±1.19 pmol/l; P = 0.043). In the univariate analysis, the elevated OPG concentration at baseline was associated with an increased risk and earlier occurrence of clinical deterioration (hazard ratio, 1.43; 95% confidence interval, 1.06-1.9; P = 0.017).. Concentrations of sRANKL and OPG are elevated in patients with PAH and are associated with indicators of disease severity and prognosis. sRANKL is a better discriminant between PAH and LVHF than OPG. The baseline OPG concentration is significantly associated with adverse outcomes in patients with PAH.

Topics: Biomarkers; Female; Humans; Hypertension, Pulmonary; Inflammation; Male; Osteoprotegerin

Inflammatory mechanisms are proposed to play a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have described PAH in fat-fed apolipoprotein E knockout (ApoE(-/-)) mice. We have reported that signaling in interleukin-1-receptor-knockout (IL-1R1(-/-)) mice leads to a reduction in diet-induced systemic atherosclerosis. We subsequently hypothesized that double-null (ApoE(-/-)/IL-1R1(-/-)) mice would show a reduced PAH phenotype compared with that of ApoE(-/-) mice. Male IL-1R1(-/-), ApoE(-/-), and ApoE(-/-)/IL-1R1(-/-) mice were fed regular chow or a high-fat diet (Paigen diet) for 8 weeks before phenotyping for PAH. No abnormal phenotype was observed in the IL-1R1(-/-) mice. Fat-fed ApoE(-/-) mice developed significantly increased right ventricular systolic pressure and substantial pulmonary vascular remodeling. Surprisingly, ApoE(-/-)/IL-1R1(-/-) mice showed an even more severe PAH phenotype. Further molecular investigation revealed the expression of a putative, alternatively primed IL-1R1 transcript expressed within the lungs but not aorta of ApoE(-/-)/IL-1R1(-/-) mice. Treatment of ApoE(-/-) and ApoE(-/-)/IL-1R1(-/-) mice with IL-1-receptor antagonist prevented progression of the PAH phenotype in both strains. Blocking IL-1 signaling may have beneficial effects in treating PAH, and alternative IL-1-receptor signaling in the lung may be important in driving PAH pathogenesis.

Topics: Animals; Apolipoproteins E; Biomarkers; Diet, High-Fat; Disease Progression; Feeding Behavior; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Osteoprotegerin; Phenotype; Pulmonary Artery; Receptors, Interleukin-1; TNF-Related Apoptosis-Inducing Ligand; Up-Regulation; Ventricular Function, Right; Ventricular Remodeling

Pulmonary artery smooth muscle cell (PA-SMC) migration and proliferation are key processes in the pathogenesis of pulmonary arterial hypertension (PAH). Recent information suggests that abnormalities in the bone morphogenetic protein (BMP) receptor 2 (BMP-R2) signaling pathway are important in PAH pathogenesis. It remains unclear whether and how this pathway interacts with, for example, serotonin (5-HT) and inflammation to trigger and/or sustain the development of PAH. The secreted glycoprotein osteoprotegerin (OPG) is emerging as an important regulatory molecule in vascular biology and is modulated by BMPs, 5-HT, and interleukin-1 in other cell types. However, whether OPG is expressed by PA-SMCs within PAH lesions and plays a role in PAH is unknown. Immunohistochemistry of human PAH lesions demonstrated increased OPG expression, and OPG was significantly increased in idiopathic PAH patient serum. Recombinant OPG stimulated proliferation and migration of PA-SMCs in vitro, and BMP-R2 RNA interference increased OPG secretion. Additionally, both 5-HT and interleukin-1 also increased OPG secretion. These data are the first to demonstrate that OPG is increased in PAH and that it can regulate PA-SMC proliferation and migration. OPG may provide a common link between the different pathways associated with the disease, potentially playing an important role in the pathogenesis of PAH.

Topics: Adult; Aged; Cell Proliferation; Cells, Cultured; Female; Humans; Hypertension, Pulmonary; Interleukin-1; Male; Middle Aged; Models, Biological; Mutation; Myocytes, Smooth Muscle; Osteoprotegerin; Pulmonary Artery