Contribution of peptidyl prolyl isomerase (Pin1) to development of pulmonary hypertension via pulmonary vascular endothelial cell dysfunction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Sakai ◽  
H Maruyama ◽  
M Ieda
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Western Blot ◽  
Caspase 3 ◽  
Pulmonary Arterial Pressure ◽  
Funding Source ◽  
Enos Expression ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is thought to be a major contributor to overall pathogenesis of vasculopathy seen in pulmonary hypertension (PH), which is manifested by the impaired release of nitric oxide (NO) generated through endothelial nitric oxide synthase (eNOS) in endothelial cells. Activation of human eNOS is regulated by phosphorylation at multiple sites including Thr33 and Ser114, which residues are followed by Pro. The peptidyl isomerase Pin1 specifically isomerizes the phospho-protein having Ser/Thr-Pro bond and regulates their activity. Pin1 is involved in proliferation, cell cycle, and apoptosis in cancer, by isomerizing some functional molecules such as JNK, JUN, cyclin D, BAX, etc. However, it is controversial whether direct interaction of Pin1 with eNOS and how eNOS activity is altered by Pin1, especially in PH. Purpose We aimed to clarify whether Pin1 contributes to the PH development using Pin1 knockout mice and Pin1 affects the expression of phosphorylated eNOS (p-eNOS) molecule and pulmonary arterial endothelial cell (PAEC) apoptosis. Methods and results Wild (WT) and Pin1-deficient mice (KO) were exposed to hypoxia (10% O2) or normoxia for 3 weeks to generate hypoxia-induced PH. Hypoxia-inducible factor (HIF1α) expression in lungs was significantly enhanced in WT-hypoxia (WH, n=6) and KO-hypoxia (KH, n=6), suggesting that hypoxic response was certainly occurred in these mice. Pulmonary arterial pressure did not elevate in KH compared with KO-normoxia (KN, n=6) and WT-normoxia (WN, n=6), it was significantly increased only in WH (P<0.01), indicating that KO did not develop PH by hypoxia. The gain of RV weight was parallel to the increase of pulmonary arterial pressure. Western blot showed that p-eNOS expression in lungs was significantly decreased in WH compared to WN, however, the expression was not different between KH and KN. It suggests that Pin1 plays a regulatory role in p-eNOS expression in hypoxic response. In cultured PAECs, the expression of p-eNOS and eNOS was markedly increased by siRNA-mediated Pin1 knockdown. Immunoprecipitation study showed the possibility of Pin1 binding to p-eNOS molecule. Apoptosis evaluated by caspase-3/7 activity by fluorescent assay and cleaved caspase-3 expression by Western blot was significantly increased by Pin1 overexpression in PAECs; however, it was significantly decreased by Pin1 knockdown. Moreover, the exaggeration of apoptosis induced by doxorubicin was markedly increased by Pin1 overexpression compared with control in PAECs; however, it was clearly suppressed by Pin1 knockdown. Conclusion This study suggests that endogenous Pin1 contributes to the development of PH partly via the dysfunction of PAECs, that is, by the interference with p-eNOS expression and by the increase of apoptosis inducibility to external stimuli. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

scholarly journals Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension

2021 ◽  
Vol 118 (17) ◽  
pp. e2023130118
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
Yen-Lin Chen ◽  
Thomas M. Baker ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Lung Edema ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1–TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1–TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Abstract 2305: Pulmonary Vascular Reactivity And Prognosis In Patients With Chronic Thromboembolic Pulmonary Hypertension

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nika Skoro-Sajer ◽  
Nicklas Hack ◽  
Roela Sadushi ◽  
Johannes Jakowitsch ◽  
Diana Bonderman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Vascular Reactivity ◽  
Pulmonary Arterial Pressure ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Mean Pulmonary Arterial Pressure ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Relative Change

Hemodynamic responder status defined as an acute decrease of mean pulmonary arterial pressure (mPAP)>10mmHg and below 40mmHg is associated with improved outcome in patients (pts) with pulmonary arterial hypertension (PAH). Pulmonary vascular reactivity to nitric oxide (NO) is controversial in chronic thromboembolic pulmonary hypertension (CTEPH). We speculated that the magnitude of the acute decrease in mean pulmonary artery pressure (mPAP) after exposure to NO might reflect the degree of small vessel disease in CTEPH and thus, affect long-term outcome. Methods: Right heart catheterization was performed in 62 (55  ± 15 years, 32 female) pts with major-vessel CTEPH, at baseline and during inhalation of 40ppm NO. Within 25±15 days patients underwent pulmonary endarterectomy (PEA). Pts were followed for 11.3±26 months. Predictors of survival were analyzed by Cox regression analysis, and survival was described by Kaplan-Meier curves. Results: Significant reductions in mean pulmonary arterial pressure (mPAP; p<0.001), pulmonary vascular resistance (PVR; p<0.001) and an increase in mixed venous oxygen saturation following NO inhalation were demonstrated (p<0.001) by a paired t-test. Stepwise multivariate analysis revealed the relative change of PVR after NO inhalation as a predictor of survival. Patients whose PVR during NO inhalation declined below 789.8 dynes.s.cm-5 had significantly better outcome than patients with above median PVR. There was a strong negative correlation between the relative change of PVR under NO and recurrent pulmonary hypertension after PEA (p=0.02). Conclusions: Patients with operable CTEPH demonstrated acute pulmonary vascular reactivity, mostly not corresponding to a complete responder status, but accounting for a wide range of decreases of mPAP [change of mPAP (%) (−10.9±14)] and PVR [change of PVR (%) (−17 ±15)]. Reduction of PVR under 800 dynes.s.cm-5 after inhalation of NO was associated with better outcome. Responsiveness to inhaled nitric oxide is a predictor for mid-term survival in adult patients with CTEPH undergoing PEA.

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

1996 ◽  
Vol 8 (3) ◽  
pp. 431 ◽  
Author(s):  
V DeMarco ◽  
JW Skimming ◽  
TM Ellis ◽  
S Cassin
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Circulation ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Minimum Concentration ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inhaled No

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Inhibition of phosphodiesterase 1 augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs with acute pulmonary hypertension

2006 ◽  
Vol 290 (4) ◽  
pp. L723-L729 ◽  
Author(s):  
Oleg V. Evgenov ◽  
Cornelius J. Busch ◽  
Natalia V. Evgenov ◽  
Rong Liu ◽  
Bodil Petersen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Selective Inhibition ◽  
Pulmonary Vasodilation ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Inhaled No

Phosphodiesterase 1 (PDE1) modulates vascular tone and the development of tolerance to nitric oxide (NO)-releasing drugs in the systemic circulation. Any role of PDE1 in the pulmonary circulation remains largely uncertain. We measured the expression of genes encoding PDE1 isozymes in the pulmonary vasculature and examined whether or not selective inhibition of PDE1 by vinpocetine attenuates pulmonary hypertension and augments the pulmonary vasodilator response to inhaled NO in lambs. Using RT-PCR, we detected PDE1A, PDE1B, and PDE1C mRNAs in pulmonary arteries and veins isolated from healthy lambs. In 13 lambs, the thromboxane A2 analog U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mmHg. Four animals received an intravenous infusion of vinpocetine at incremental doses of 0.3, 1, and 3 mg·kg−1·h−1. In nine lambs, inhaled NO was administered in a random order at 2, 5, 10, and 20 ppm before and after an intravenous infusion of 1 mg·kg−1·h−1 vinpocetine. Administration of vinpocetine did not alter pulmonary and systemic hemodynamics or transpulmonary cGMP or cAMP release. Inhaled NO selectively reduced mean pulmonary arterial pressure, pulmonary capillary pressure, and pulmonary vascular resistance index, while increasing transpulmonary cGMP release. The addition of vinpocetine enhanced pulmonary vasodilation and transpulmonary cGMP release induced by NO breathing without causing systemic vasodilation but did not prolong the duration of pulmonary vasodilation after NO inhalation was discontinued. Our findings demonstrate that selective inhibition of PDE1 augments the therapeutic efficacy of inhaled NO in an ovine model of acute chemically induced pulmonary hypertension.

Nitric oxide given via a head-box for persistent neonatal pulmonary hypertension

1995 ◽  
Vol 5 (1) ◽  
pp. 88-90
Author(s):  
Paul H. Martin ◽  
Narayanswami Sreeram ◽  
Andy J. Petros
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Persistent Pulmonary Hypertension ◽  
Severe Hypoxemia ◽  
Echocardiographic Parameters ◽  
Pulmonary Arterial

AbstractA neonate presenting with persistent pulmonary hypertension and severe hypoxemia was treated with nitric oxide administered into a head-box. Improvement of clinical, biochemical and echocardiographic parameters were observed during therapy, suggesting an acute decrease of pulmonary arterial pressure. It is feasible to administer nitric oxide to non-ventilated neonates provided all recommended safety precautions are observed

Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb

1993 ◽  
Vol 265 (4) ◽  
pp. H1318-H1325 ◽  
Author(s):  
J. Wong ◽  
P. A. Vanderford ◽  
J. R. Fineman ◽  
R. Chang ◽  
S. J. Soifer
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Newborn Lamb ◽  
Endothelin 1 ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial ◽  
Dose Dependent Decrease ◽  
Dose Dependent

The vascular endothelium mediates, in part, pulmonary vascular tone. Because endothelin-1 (ET-1), a paracrine hormone produced by vascular endothelial cells, has vasoactive properties, we investigated the hemodynamic effects of intrapulmonary injections of ET-1 in eight intact newborn lambs at rest and during pulmonary hypertension. At rest, ET-1 (50-1,000 ng/kg) did not change pulmonary arterial pressure. During pulmonary hypertension induced by the infusion of U46619 (a thromboxane A2 mimic), ET-1 (50-1,000 ng/kg) produced a selective dose-dependent decrease in pulmonary arterial pressure (5.8 +/- 3.9 to 32.9 +/- 6.9%; P < 0.05). Similarly, during pulmonary hypertension induced by alveolar hypoxia, ET-1 (50-500 ng/kg) produced a selective dose-dependent decrease in pulmonary arterial pressure (7.2 +/- 3.6 to 26.1 +/- 3.3%; P < 0.05). The decrease in pulmonary arterial pressure produced by ET-1 (250 ng/kg) was attenuated by N omega-nitro-L-arginine (an inhibitor of endothelium-derived nitric oxide synthesis, 23.7 +/- 3.4 vs. 12.5 +/- 4.7%; P < 0.05) and by glibenclamide (an ATP-gated potassium-channel blocker, 25.2 +/- 5.0 vs. 9.6 +/- 5.3%; P < 0.05) but not by meclofenamic acid (an inhibitor of prostaglandin synthesis). ET-1 is a pulmonary vasodilator during pulmonary hypertension in the intact newborn lamb. The vasodilating properties are mediated, in part, by release of endothelium-derived nitric oxide, and by activation of ATP-gated potassium channels.

MO746CARDIAC REMODELING AND PULMONARY HYPERTENSION IN HEMODIALYSIS PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Ekaterina Borodulina ◽  
Alexander M Shutov
Keyword(s):  
Pulmonary Hypertension ◽  
Left Ventricular Hypertrophy ◽  
Arterial Pressure ◽  
Ventricular Hypertrophy ◽  
Pulmonary Arterial Pressure ◽  
Hemodialysis Patients ◽  
Left Ventricular ◽  
Hemodialysis Treatment ◽  
Systolic Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

Abstract Background and Aims An important predictor of cardiovascular mortality and morbidity in hemodialysis patients is left ventricular hypertrophy. Also, pulmonary hypertension is a risk factor for mortality and cardiovascular events in hemodialysis patients. The aim of this study was to investigate cardiac remodeling and the dynamics of pulmonary arterial pressure during a year-long hemodialysis treatment and to evaluate relationship between pulmonary arterial pressure and blood flow in arteriovenous fistula. Method Hemodialysis patients (n=88; 42 males, 46 females, mean age was 51.7±13.0 years) were studied. Echocardiography and Doppler echocardiography were performed in the beginning of hemodialysis treatment and after a year. Echocardiographic evaluation was carried out on the day after dialysis. Left ventricular mass index (LVMI) was calculated. Left ventricular ejection fraction (LVEF) was measured by the echocardiographic Simpson method. Arteriovenous fistula flow was determined by Doppler echocardiography. Pulmonary hypertension was diagnosed according to criteria of Guidelines for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology. Results Pulmonary hypertension was diagnosed in 47 (53.4%) patients. Left ventricular hypertrophy was revealed in 71 (80.7%) patients. Only 2 (2.3%) patients had LVEF&lt;50%. At the beginning of hemodialysis correlation was detected between systolic pulmonary arterial pressure and LVMI (r=0.52; P&lt;0.001). Systolic pulmonary arterial pressure negatively correlated with left ventricular ejection fraction (r=-0.20; P=0.04). After a year of hemodialysis treatment LVMI decreased from 140.49±42.95 to 123.25±39.27 g/m2 (р=0.006) mainly due to a decrease in left ventricular end-diastolic dimension (from 50.23±6.48 to 45.13±5.24 mm, p=0.04) and systolic pulmonary arterial pressure decreased from 44.83±14.53 to 39.14±10.29 mmHg (р=0.002). Correlation wasn’t found between systolic pulmonary arterial pressure and arteriovenous fistula flow (r=0.17; p=0.4). Conclusion Pulmonary hypertension was diagnosed in half of patients at the beginning of hemodialysis treatment. Pulmonary hypertension in hemodialysis patients was associated with left ventricular hypertrophy, systolic left ventricular dysfunction. After a year-long hemodialysis treatment, a regress in left ventricular hypertrophy and a partial decrease in pulmonary arterial pressure were observed. There wasn’t correlation between arteriovenous fistula flow and systolic pulmonary arterial pressure.

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