BMP signaling controls PASMC KV channel expression in vitro and in vivo

2006 ◽  
Vol 290 (5) ◽  
pp. L841-L848 ◽  
Author(s):  
Katharine A. Young ◽  
Charles Ivester ◽  
James West ◽  
Michelle Carr ◽  
David M. Rodman
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Transgenic Mice ◽  
Pulmonary Artery Pressure ◽  
Systolic Pressure ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Artery Pressure ◽  
Channel Expression

Bone morphogenetic proteins (BMPs) have been implicated in the pathogenesis of familial pulmonary arterial hypertension. The type 2 receptor (BMPR2) is required for recognition of all BMPs. Transgenic mice with a smooth muscle cell-targeted mutation in this receptor (SM22-tet-BMPR2delx4+) developed increased pulmonary artery pressure, associated with a modest increase in arterial muscularization, after 8 wk of transgene activation (West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, and Rodman DM. Circ Res 94: 1109–1114, 2004). In the present study, we show that these transgenic mice developed increased right ventricular pressures after only 1 wk of transgene activation, without significant remodeling of the vasculature. We then tested the hypothesis that the increased pulmonary artery pressure due to loss of BMPR2 signaling was mediated by reduced KV channel expression. There was decreased expression of KV1.1, KV1.5, and KV4.3 mRNA isolated from whole lung. Western blot confirmed decreased KV1.5 protein in these lungs. Human pulmonary artery smooth muscle cells (PASMC) treated with recombinant BMP2 had increased KV1.5 protein and macroscopic KV current density, which was blocked by anti-KV1.5 antibody. In vivo, nifedipine, a selective L-type Ca2+ channel blocker, reduced RV systolic pressure in these dominant-negative BMPR2 mice to levels seen in control animals. This suggests that activation of L-type Ca2+ channels caused by reduced KV1.5 mediates increased pulmonary artery pressure in these animals. These studies suggest that BMP regulates KV channel expression and that loss of this signaling pathway in PASMC through a mutation in BMPR2 is sufficient to cause pulmonary artery vasoconstriction.

Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle

2007 ◽  
Vol 292 (6) ◽  
pp. L1473-L1479 ◽  
Author(s):  
Moira Hagen ◽  
Karen Fagan ◽  
Wolfgang Steudel ◽  
Michelle Carr ◽  
Kirk Lane ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transgenic Mice ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Second Hit ◽  
Protein Receptor ◽  
Bmp Pathway

The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a “second hit.” There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38MAPK inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.

Effect of acute lower respiratory tract infection on pulmonary artery pressure in children with post-tricuspid left-to-right shunt

2021 ◽  
pp. 1-5
Author(s):  
Sakshi Sachdeva ◽  
Shyam S. Kothari ◽  
Saurabh K. Gupta ◽  
Sivasubramanian Ramakrishnan ◽  
Anita Saxena
Keyword(s):  
Tract Infection ◽  
Pulmonary Artery ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Lower Respiratory Tract Infection ◽  
Pulmonary Artery Pressure ◽  
Lower Respiratory Tract ◽  
Systolic Pressure ◽  
Pulmonary Artery Systolic Pressure ◽  
Artery Pressure

Abstract We sought to examine the influence of clinically severe lower respiratory tract infection on pulmonary artery pressure in children having CHD with post-tricuspid left-to-right shunt, as it may have physiological and clinical implications. In a prospective single-centre observational study, 45 children with post-tricuspid left-to-right shunt and clinically severe lower respiratory tract infection were evaluated during the illness and 2 weeks after its resolution. Pulmonary artery systolic pressure was estimated non-invasively using shunt gradient by echocardiography and systolic blood pressure measured non-invasively. Median pulmonary artery systolic pressure during lower respiratory tract infection was only mildly (although statistically significantly) elevated during lower respiratory tract infection [60 (42–74) versus 53 (40–73) mmHg, (p < 0.0001)]. However, clinically significant change in pulmonary artery systolic pressure defined as the increase of >10 mmHg was present in only 9 (20%) patients. In the absence of hypoxia or acidosis, only a small minority (9%, n = 4) showed significant pulmonary artery systolic pressure rise >10 mmHg. In the absence of hypoxia or acidosis, severe lower respiratory tract infection in patients with acyanotic CHD results in only mild elevation of pulmonary artery systolic pressure in most of the patients.

Comparison of methods of measuring pulmonary artery pressure

1997 ◽  
Vol 6 (4) ◽  
pp. 324-332 ◽  
Author(s):  
JL Lundstedt
Keyword(s):  
Mechanical Ventilation ◽  
Cardiac Surgery ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Spontaneous Breathing ◽  
Systolic Pressure ◽  
Graphic Method ◽  
Difference Scores ◽  
Artery Pressure ◽  
The Difference

BACKGROUND: Pulmonary artery waveforms fluctuate because of changes in intrathoracic pressure caused by respirations. Monitoring system algorithms determine digital displays of pressure measurements on the basis of recognition, analysis, and comparison of consecutive waveforms. OBJECTIVE: To compare three methods of measuring pulmonary artery pressure during mechanical ventilation and spontaneous breathing in cardiac surgery patients with stable hemodynamics. METHODS: Pulmonary artery pressure was measured during mechanical ventilation after cardiac surgery in 53 patients; 37 of the patients were studied again after extubation. Three monitoring methods were compared: graphic strip recording, the "stop cursor" (monitor screen freezing) method, and digital-display recording. Difference scores were calculated between the methods and analyzed for frequency and direction. RESULTS: All comparisons showed differences of at least +/-3 mm Hg in measurements obtained with the three methods. During mechanical ventilation, the digital and graphic measurements of systolic pressure varied most often; 57% (30/53) of the comparisons had difference scores of at least +/-3 mm Hg. The cursor and graphic measurements of diastolic pressures varied least often; 6% (3/53) of the comparisons had difference scores of at least +/-3 mm Hg. As expected, the digital method most often gave higher results than the graphic method. During spontaneous breathing, measurements of systolic pressure varied more often (38% to 53%) than did measurements of diastolic pressure (12% to 37%). Unexpectedly, for systolic pressures, the difference between digital and graphic measurements was 3 mm Hg or more 30% (11/37) of the time, and the difference between cursor and graphic measurements was 3 mm Hg or more 53% (17/32) of the time. CONCLUSIONS: Because of physiological and technical influences, measurements of systolic and diastolic pressures in the pulmonary artery made with the digital and cursor methods were not as reliable as measurements made with the graphic method. The findings support continued use of the graphic method for accurate measurements of pulmonary artery pressure.

scholarly journals Targeted blocking of gene expression for CGRP receptors elevates pulmonary artery pressure in hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L86-L96 ◽  
Author(s):  
Xin Qing ◽  
Ingegerd M. Keith
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Pulmonary Circulation ◽  
Protective Role ◽  
Cgrp Receptor ◽  
Sprague Dawley ◽  
Artery Pressure ◽  
Receptor Component ◽  
Technical Control

We previously described the protection by calcitonin gene-related peptide (CGRP) against hypoxic pulmonary hypertension. Here, we examine the roles of its putative receptor RDC-1 and receptor activity-modifying protein (RAMP) 1 in mediating this protection by selectively inhibiting their synthesis. RAMP1 is an accessory protein for another putative CGRP receptor, calcitonin receptor-like receptor. Antisense oligodeoxyribonucleotides (ASODNs, 5 mg·kg-1·day-1 or 5 and 10 mg·kg-1·day-1 for RDC-1) targeting RAMP1 and RDC-1 mRNAs were chronically infused to the pulmonary circulation of male Sprague-Dawley rats during 7 days of normoxia or hypobaric hypoxia (380 mmHg), and α-CGRP ASODN was used as a technical control. CGRP, RAMP1, and RDC-1 ASODNs significantly elevated pulmonary artery pressure (PPA) in chronic hypoxic rats compared with hypoxic mismatched ASODN (MMODN) and saline vehicle controls. CGRP and RAMP1 ASODNs raised PPA in normoxic rats briefly exposed to 10% O2 above MMODN and saline controls. Moreover, normoxic rats treated with CGRP ASODN had higher basal pulmonary vascular tone compared with controls. These data confirm the protective role of CGRP in the pulmonary circulation and suggest that endogenous RAMP1 and RDC-1 are essential in regulation of PPA in hypoxia. This is the first in vivo evidence supporting RDC-1 and RAMP1 as functional CGRP receptor and receptor component.

Association of Plasma Cell-Free Hemoglobin with Physiological Measures of Nitric Oxide Responsiveness and Estimated Pulmonary Artery Systolic Pressure: Requirement for Rigorously Optimized Blood Processing Variables

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3253-3253
Author(s):  
Laurel G. Mendelsohn ◽  
Susan Yuditskaya ◽  
Xunde Wang ◽  
Wasnard Victor ◽  
Katherine Corbin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Free Hemoglobin ◽  
Artery Pressure ◽  
Plasma Hemoglobin ◽  
Processing Variables

Abstract Abstract 3253 Background: Accurate plasma hemoglobin (PHb) measurements are needed to investigate a model proposing a link between intravascular hemolysis and decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD). Artifactual hemolysis hypothetically can produce excessive noise that might obscure the signal and lead to misinterpretation of data. We systematically studied possible blood processing variables that could cause artifactual hemolysis to obscure in vivo levels of free hemoglobin in adults with SCD. Methods: We systematically compared the effects on PHb measured by ELISA of anticoagulant type, Vacutainer materials and processing time on the same blood specimens from healthy controls and adults with SCD divided into aliquots that were then processed using a variety of in vitro conditions. We analyzed the results of PHb measurements from archived specimens from 467 SCD patients. We evaluated in greater detail plasma specimens collected and processed at bedside from 44 patients with SCD under optimal conditions: drawn from indwelling wide-bore brachial artery catheters by minimal negative pressure into heparinized syringes, gently transferred to tubes for centrifugation within 5 minutes, evaluating the associations of PHb levels from these optimally processed samples with relevant in vivo physiological measurements. Results: Analysis of specimens from healthy control subjects (n=10) and adults with SCD (n=10) for each experiment, split into aliquots to test each variable under defined conditions yielded significant evidence indicating that: (1) arterial catheter syringe specimens are superior to conventional Vacutainer venipuncture specimens; (2) heparin is superior to EDTA anticoagulant; (3) glass tubes are superior to plastic tubes; (4) processing in 2 hours or less is superior to longer processing times. Comparison of 467 archived EDTA plasma specimens processed under comparably variable conditions provided results consistent with the bench top results, confirming the importance of these processing variables on research specimens. Conventional venipuncture EDTA Vacutainer tubes with conventional processing yielded median PHb levels four-fold that of arterial catheter heparin syringe specimens processed at bedside, suggesting that on average 75% of the PHb in conventional specimens may represent background noise and only 25% of the PHb level may represent in vivo free hemoglobin. Blood specimens were collected and processed by the optimal conditioned defined by the preceding experiments from 44 adults with sickle cell anemia. This set of specimens yielded a median PHb level of 6.07μM (CI95=5.27–7.03μM). PHb correlated significantly with blunting of vasodilation in vivo after brachial artery infusion of each of three graded doses of the NO donor sodium nitroprusside (SNP), an indicator of vascular NO responsiveness; at doses of 0.8μg/min(r=−0.46 p=0.0022), 1.6μg/min (r=−0.41, p=0.0082), and 3.2μg/min (r=−0.46, p=0.0024). Quartile analysis revealed a significant difference in forearm blood flow response across all doses of SNP among the highest, middle, and lowest PHb quartiles (p=0.0386). PHb also correlated significantly with tricuspid regurgitant velocity (R=0.37, p=0.0147), suggesting a significant association with Doppler echocardiography estimates of pulmonary artery pressure. A limited number of patients from this specimen pool (n=7) subsequently underwent clinically indicated right heart catheterization. There was a trend in this small subset correlating PHb with mean pulmonary artery pressure (r=0.61, p=0.1482). Conclusions: Plasma hemoglobin levels collected and processed under optimal conditions show statistically significant associations with in vivo physiological measures of nitric oxide responsiveness and echocardiographically estimated pulmonary artery pressure, with supportive trends from right heart catheterization in a limited subgroup of patients with SCD. This supports a role for plasma hemoglobin as a biomarker of nitric oxide resistance and pulmonary hypertension in SCD. Conventional phlebotomy into Vacutainer tubes introduces a high background level of artifactual ex vivo hemolysis in SCD specimens that is capable of obscuring these associations, especially if processing is delayed 2 hours or more. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pulmonary embolism attenuation is a potential imaging biomarker for pulmonary artery hemodynamic improvement after catheter-directed thrombolysis

2018 ◽  
Vol 23 (2) ◽  
pp. 134-138
Author(s):  
Edwin A Takahashi ◽  
Christopher J Reisenauer ◽  
Andrew H Stockland ◽  
Haraldur Bjarnason ◽  
Melissa J Neisen ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Pulmonary Embolism ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Systolic Pressure ◽  
Imaging Biomarker ◽  
Spearman Correlation ◽  
Ventricular Systolic Pressure ◽  
Artery Pressure ◽  
Catheter Directed Thrombolysis

This study examined the potential correlation between pulmonary embolism (PE) attenuation on computed tomography pulmonary angiography (CTPA) and pulmonary artery hemodynamic response to catheter-directed thrombolysis (CDT) in 10 patients with submassive PE. Treatment parameters, PE attenuation, clot burden, computed tomography signs of right ventricle dysfunction and right ventricular systolic pressure at echocardiography were retrospectively analyzed to determine correlation with pulmonary artery pressure improvement using Spearman correlation. A single reader, blinded to the treatment results, measured PE attenuation of all patients. There was a significant positive correlation between PE attenuation and absolute pulmonary artery pressure improvement with a Spearman correlation of 0.741, p=0.014. When attenuation was greater than or equal to the median (44.5 HU, n=5), CDT was associated with significantly better pulmonary artery pressure improvement ( p=0.037). Clot attenuation at CTPA may be a potential imaging biomarker for predicting pulmonary artery pressure improvement after CDT.

Abstract 16599: Impaired Right Ventricular Contractile Reserve During Exercise in Endurance Athletes With Right Ventricular Arrhythmias

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Guido Claessen ◽  
Andre La Gerche ◽  
Jens-Uwe Voigt ◽  
Steven Dymarkowski ◽  
Luc Van Hees ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Right Ventricular ◽  
Pulmonary Artery Pressure ◽  
Ventricular Arrhythmias ◽  
Systolic Pressure ◽  
Endurance Athletes ◽  
Contractile Reserve ◽  
Systolic Pulmonary Artery Pressure ◽  
Exercise Echocardiography ◽  
Artery Pressure

Introduction: Ventricular arrhythmias in endurance athletes (EAs) frequently originate from a mildly dysfunctional right ventricle (RV). We evaluated whether RV dysfunction in EAs with ventricular arrhythmias of RV origin (EA-VAs) becomes more apparent during exercise than at rest. Methods: Ten healthy EAs, 7 healthy non-athletes (NAs) and 17 EA-VAs (8 with ICD) first underwent cardiopulmonary exercise testing to determine maximal power (Pmax). Then, exercise echocardiography was performed at 25%, 50% and 66% of Pmax to measure the RV end-systolic pressure-area ratio (ESPAR), a surrogate of RV contractility, which was calculated as systolic pulmonary artery pressure/RV end-systolic area. Finally, all subjects without ICD underwent cardiac MRI during supine bicycle exercise at similar workloads with simultaneous invasive pulmonary artery pressure measurement to determine the RV end-systolic pressure-volume ratio (SP/ESV). Results: At rest, RV ESPAR was similar in EA-VAs relative to NAs (P=0.1), although slightly lower than in NAs (P=0.02). During exercise, EA-VAs had an impaired increase in RV ESPAR compared to both EAs and NAs (interaction P<0.0001; Figure 1A). Also the slopes of RV ESPAR to absolute workload (in Watts) were lower in EA-VAs than in EAs and NAs (P<0.0001) and correlated highly with the slopes of RV SP/ESV to workload obtained by MRI and invasive pressure measures (R=0.75; P<0.0001). Figure 1B shows that resting and peak exercise RV ESPAR cutoffs of 1.4 and 3.9 mmHg/cm 2 had a sensitivity of 77% and 79% and specificity of 80% and 100%, respectively, to identify EA-VAs. Conclusion: EA-VAs have impaired RV contractility which is evident during exercise but hardly at rest. This strengthens the association between RV arrhythmias and functional impairment. Our data suggest that exercise echocardiography is sufficiently accurate to determine RV contractile reserve in a non-invasive manner and may assist in risk stratification of RV remodeling in EAs.

scholarly journals Prevalence and Predictors of Elevated Pulmonary Artery Pressure in Nigerian Children with Sickle Cell Anaemia

2020 ◽  
pp. 48-59
Author(s):  
Usman Muhammad Sani ◽  
Usman Muhammad Waziri ◽  
Nma M. Jiya ◽  
Hamidu Ahmed ◽  
Khadijat Omeneke Isezuo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Artery Pressure ◽  
Sickle Cell ◽  
Sickle Cell Anaemia ◽  
Reticulocyte Count ◽  
Systolic Pressure ◽  
Full Blood Count ◽  
High Systolic Blood Pressure ◽  
Artery Pressure

Background: Sickle Cell Anaemia (SCA) is the most common inherited disorder in Nigeria. Pulmonary Hypertension (PH) is a known complication of SCA that commences from childhood and progresses as they grow older. Aim: To determine the prevalence and predictors of elevated pulmonary artery pressure (PAP) in children with SCA. Study Design: This is an analytical cross-sectional study. Methods: Three hundred subjects with SCA in steady state and 300 HbAA controls, aged 6 months – 15 years, were enrolled into the study. Children with SCA were recruited by simple random sampling, from the Paediatric Sickle Cell Clinic, Usmanu Danfodiyo University Teaching Hospital, Sokoto. All the children had clinical evaluation, echocardiography, full blood count and reticulocyte count. Pulmonary artery systolic pressure (PASP) and mean pulmonary artery pressure (MPAP) were determined by measurement of tricuspid regurgitant velocity (TRV) and mean gradient (MG) respectively.  Results: Seventy-two children with SCA (24.0%) had elevated PAP (defined as TRV ≥ 2.5 m /s) while only 9 (3.0%) had pulmonary hypertension (defined as MPAP ≥ 25 mmHg). Older age (O.R = 1.03, p < 0.001), high systolic blood pressure (O.R = 1.2, p = 0.01), and high reticulocyte count (O.R = 1.33, p = 0.04) were weakly associated with increased likelihood of elevated PAP. Normal pulse oxygen saturation (SPO2 ≥ 95%, O.R = 0.4, p = 0.002) and normal heart sounds on auscultation (O.R = 0.2, p = 0.04) were associated with a reduced likelihood of elevated PAP. Presence of left parasternal heave (O.R = 8.4, p = 0.001) significantly predicted elevated PAP in children with SCA. Conclusion: PH occurs as a complication in children with SCA and certain clinical and laboratory parameters do predict this complication in children.

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