Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial forms of human pulmonary arterial hypertension (FPAH) have been linked to mutations in bone morphogenetic protein (BMP) type II receptors (BMPR2s), yet the downstream targets of these receptors remain obscure. Here we show that pulmonary vascular lesions from patients harboring BMPR2 mutations express high levels of tenascin-C (TN-C), an extracellular matrix glycoprotein that promotes pulmonary artery (PA) smooth muscle cell (SMC) proliferation. To begin to define how TN-C is regulated, PA SMCs were cultured from normal subjects and from those with FPAH due to BMPR2 mutations. FPAH SMCs expressed higher levels of TN-C than normal SMCs. Similarly, expression of Prx1, a factor that drives TN-C transcription, was elevated in FPAH vascular lesions and SMCs derived thereof. Furthermore, Prx1 and TN-C promoter activities were significantly higher in FPAH vs. normal SMCs. To delineate how BMPR2s control TN-C, we focused on receptor (R)-Smads, downstream effectors activated by wild-type BMPR2s. Nuclear localization and phosphorylation of R-Smads was greater in normal vs. FPAH SMCs. As well, indirect blockade of R-Smad signaling with a kinase-deficient BMP receptor Ib upregulated TN-C in normal SMCs. Because ERK1/2 MAPKs inhibit the transcriptional activity of R-Smads, and because ERK1/2 promotes TN-C transcription, we determined whether ERK1/2 inhibits R-Smad signaling in FPAH SMCs and whether this activity is required for TN-C transcription. Indeed, ERK1/2 activity was greater in FPAH SMCs, and inhibition of ERK1/2 resulted in nuclear localization of R-Smads and inhibition of TN-C. These studies define a novel signaling network relevant to PAH underscored by BMPR2 mutations.
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PMID:Tenascin-C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. 1678 55

Samples of lung tissue, taken at time of lung transplant, from 13 Dutch Caucasian patients with idiopathic pulmonary arterial hypertension (iPAH) and 14 patients with non-idiopathic PAH were studied for the presence of human herpes virus-8 (HHV-8). By immunohistochemical staining, in none of patients expression of HHV-8 latency-associated nuclear antigen 1 (LANA-1) was demonstrated. Using two nested polymerase chain reactions (PCR) to amplify part of the open reading frame (ORF) 65 and ORF 73, we failed to detect HHV-8 DNA in all samples studied. These results argue strongly against a role for HHV-8 in the pathogenesis of iPAH.
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PMID:Idiopathic pulmonary arterial hypertension in Dutch Caucasian patients is not associated with human herpes virus-8 infection. 1701 70

Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-beta. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-beta signaling and altered cellular responses to TGF-beta. The likely mechanism involves an interaction between BMP and TGF-beta-regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-beta and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.
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PMID:Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? 1706 73

With the availability of better treatment and prophylactic regimens for the infectious complications of human immunodeficiency virus (HIV), the non-infectious complications are gaining greater attention. HIV-related pulmonary arterial hypertension (HIV-PAH) is one of these. The incidence of HIV-PAH is estimated at 0.5% of HIV-infected individuals. The pathogenesis remains unclear. Patients present with symptoms as diverse as progressive shortness of breath, pedal edema, dry cough, fatigue, syncope, as well as chest pain. Chest X-ray always shows cardiomegaly and prominent pulmonary artery, and evidence of right ventricular hypertrophy can be seen from the electrocardiogram. The pulmonary arterial systolic pressure, diastolic pressure and pulmonary vascular resistance from right heart catheterization are increased. There are a few small studies showing the benefit of prostacyclin analog (epoprostenol and iloprost) and bosentan. The role of antiretrovirals remains controversial, as do those of other agents such as calcium channel blockers and anticoagulants. The prognosis of HIV-PAH is grave. Two thirds of HIV-PAH related mortality is usually secondary to consequences of pulmonary hypertension, with the worst survival noted in New York Heart Association (NYHA) functional class III-IV. The probability of survival in one series was 73%, 60% and 47% at one, two and three years, respectively.
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PMID:HIV-related pulmonary hypertension. 1719 95

Although relatively rare, pulmonary hypertension can be devastating for those individuals who are affected and has significant societal implications. The 2003 WHO classification separates PAH (idiopathic, specific disease linked) from pulmonary hypertension related to lung disease, thromboembolic disease, and pulmonary venous hypertension. Another form of pulmonary hypertension, persistent pulmonary hypertension (PPHN), occurs in the newborn. In general, PPHN is thought to be responsible for approximately 10% of admissions to neonatal intensive care units and can be a complicating factor in 5 of 1000 live births. Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are complex disorders that pose a significant threat to critically ill patients. They are usually related to direct lung injury or indirect injury from sepsis, trauma, and other disorders. Although these pulmonary disorders reflect distinct pathophysiologic mechanisms, current evidence strongly suggests that a common denominator underlying many of the established molecular and cellular elements is endothelial cell activation and dysfunction. This summary statement briefly summarizes the state of the science and suggests future avenues of public health research.
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PMID:Vascular endothelium summary statement V: Pulmonary hypertension and acute lung injury: public health implications. 1719 49

The aim of the present study was to describe a large cohort of fenfluramine-associated pulmonary arterial hypertension (fen-PAH) and its possible prognostic markers. The records of all patients with a diagnosis of fen-PAH evaluated at the present authors' centre from 1986-2004 were retrospectively studied. Baseline clinical and haemodynamic data were collected, as well as survival times. The median duration of fenfluramine exposure was 6 months, with a median of 4.5 yrs between exposure and onset of symptoms. Nine (22.5%) out of 40 patients evaluated resulted positive for the presence of germline bone morphogenetic protein receptor (BMPR) type 2 mutations. In these patients, the duration of exposure to fenfluramine was significantly lower than in patients without mutation. The median survival was 6.4 yrs, without significant difference between fen-PAH and a control group of idiopathic and familial pulmonary arterial hypertension patients referred to the present authors' centre during the same time frame and treated identically. Duration of fenfluramine exposure showed no relation to survival, while cardiac index was the only independent predictor of multivariate analysis. Fenfluramine-associated pulmonary arterial hypertension shares clinical, functional, haemodynamic and genetic features with idiopathic pulmonary arterial hypertension, as well as overall survival rates. Therefore, the present authors conclude that fenfluramine exposure characterises a potent trigger for pulmonary arterial hypertension without influencing its clinical course.
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PMID:Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. 1823 44

Pulmonary hypertension is a serious disease with a poor prognosis. Pulmonary hypertension is defined by a mean pulmonary arterial pressure over 25 mm Hg at rest or over 30 mm Hg during activity. According to the recent WHO classification from 2003 pulmonary hypertension can be categorized as pulmonary arterial hypertension, pulmonary venous hypertension, hypoxic pulmonary hypertension, chronic thromboembolic pulmonary hypertension and pulmonary hypertension from other causes. Pulmonary arterial hypertension is characterized histopathologically by vasoconstriction, vascular proliferation, in situ thrombosis, and remodeling of all 3 levels of the vascular walls. These pathologic changes result in progressive increases in the mean pulmonary artery pressure and pulmonary vascular resistance, which, if untreated leads to right-ventricular failure and death. Early in the disease process, the signs and symptoms of PAH are often nonspecific, making diagnosis challenging. Patients often present with progressively worsening dyspnea and fatigue. Patients with severe pulmonary arterial hypertension die of right heart failure. The diagnostic procedures include clinical history and physical examination, a standard chest radiography, electrocardiography, transthoracic Doppler echocardiography, pulmonary function tests, arterial blood gas analysis, ventilation and perfusion lung scan, high-resolution computed tomography of the lungs, contrast-enhanced spiral computed tomography of the lungs and pulmonary angiography, blood tests and immunology, abdominal ultrasound scan, exercise capacity assessment, and hemodynamic evaluation. Invasive and non-invasive markers of disease severity, either biomarkers or physiological parameter and tests that can be widely applied, have been proposed to reliably monitor the clinical course. Pulmonary biopsy is rarely indicated. Transthoracic echocardiography is a key screening tool in the diagnostic algorithm. Because transthoracic echocardiography is an inexpensive, easy, and reproducible method, it is the most commonly used noninvasive diagnostic tool to determine pulmonary arterial pressure. But it not only provides an estimate of pulmonary pressure at rest and during exercise, but it may also help to exclude any secondary causes of pulmonary hypertension, predict the prognosis, monitor the efficacy of specific therapeutic interventions, and detect the preclinical stage of the disease. In addition, the measurement of serum markers, such as brain natriuretic peptide (BNP), are diagnostically useful and of prognostic significance. Once the diagnosis and etiology of pulmonary hypertension have been established, several parameters can predict outcome in these patients: functional class, right ventricular function, pulmonary hemodynamics, and certain laboratory parameters. Also, exercise parameters such as walking distance, peak oxygen uptake or peak systolic blood pressure can reliable predict prognosis in these patients.
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PMID:Diagnostics in pulmonary hypertension. 1820 73

Since systemic sclerosis (SSc) also involves the heart, the aim of the present study was to evaluate possible differences in right ventricular (RV) pump function between SSc-associated pulmonary arterial hypertension (PAH; SScPAH) and idiopathic PAH (IPAH). In 13 limited cutaneous SScPAH and 17 IPAH patients, RV pump function was described using the pump function graph, which relates mean RV pressure ((RV)) and stroke volume index (SVI). Differences in pump function result in shift or rotation of the pump function graph. (RV) and SVI were measured using standard catheterisation. The hypothetical isovolumic (RV) ((RV,iso)) was estimated using a single-beat method. The pump function graph was approximated by a parabola: (RV) = (RV,iso)[1-(SVI/SVI(max))(2)], where SVI(max )is the hypothetical maximal SVI at zero (RV), enabling calculation of SVI(max). There were no differences in SVI and SVI(max). Both (RV) and (RV,iso) were significantly lower in SScPAH than in IPAH ((RV) 30.7+/-8.5 versus 41.2+/-9.4 mmHg; (RV,iso) 43.1+/-12.4 versus 53.5+/-10.0 mmHg). Since higher pressures were found at similar SVI, the difference in the pump function graph results from lower contractility in SScPAH than in IPAH. Right ventricular contractility is lower in systemic sclerosis-associated pulmonary arterial hypertension than in idiopathic pulmonary arterial hypertension.
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PMID:Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. 1821 49

Although progress has been made in treatment of pulmonary arterial hypertension, serious challenges remain. This article provides an overview of the challenges faced in treatment of PAH caused by scleroderma. It also provides a glimpse into the future, based on recent developments in the field that hold promise for enhancing the treatment of this disease.
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PMID:Treatment of pulmonary arterial hypertension due to scleroderma: challenges for the future. 1832 40

Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) has been described. We hypothesize that HHV-8 infection of pulmonary microvascular endothelial cells results in an apoptotic-resistant phenotype characteristic of severe pulmonary arterial hypertension. Our objective was to investigate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells in vitro and characterize the phenotypic effect of this infection. Human pulmonary microvascular endothelial cells were exposed to HHV-8 using two methods (direct virus and co-culture technique). The presence of lytic and latent infection was confirmed. Changes in endothelial cell gene and protein expression and effects on cellular apoptosis were measured. HHV-8 can both lytically and latently infect primary human pulmonary microvascular endothelial cells in vitro. HHV-8 infection results in significant changes in gene expression, including alterations of pathways important to cellular apoptosis. HHV-8 infection also alters expression of genes integral to the bone morphogenic protein pathway, including down-regulation of bone morphogenic protein-4. Other genes previously implicated in the development of PAH are affected by HHV-8 infection, and cells infected with HHV-8 are resistant to apoptosis.
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PMID:Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. 1858 55


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