Abstract 70: Novel Multi-target Compound, Agonist of Adenosine Receptor and Inhibitor of Phosphodiesterase 5, Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Gisele Zapata-Sudo ◽  
Allan K Alencar ◽  
Jaqueline S da Silva ◽  
Eliezer J Barreiro ◽  
Carlos A Fraga ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
Systolic Pressure ◽  
Premature Death ◽  
Treated Group ◽  
Exercise Intolerance ◽  
Vehicle Group ◽  
Ventricular Systolic Pressure ◽  
Phosphodiesterase 5

Aims: Pulmonary hypertension (PH) is a disease that results in right ventricular (RV) dysfunction and premature death. This work investigated the effects of LASSBio-1386, a compound with dual target, activation of the adenosine A 2A receptor and inhibition of phosphodiesterase 5 in rats with monocrotaline (MCT)-induced PH. Methods and Results: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were: control, MCT + vehicle (DMSO), MCT + LASSBio-1386 (100 μmol/kg/day p.o.) and MCT + Sildenafil (100 μmol/kg/day p.o.). Animals were treated with vehicle or drug for 14 days after the onset of disease (n = 6 per group). Treadmill test and transthoracic echocardiography were performed to access exercise capacity and cardiac function, respectively. Right ventricular systolic pressure (RVSP) and ratio between RV and body weight (RV/BW) were analyzed. Exercise capacity (m.kg) was reduced from 1336.2 ± 82.2(control) to 479.7 ± 75.5 (MCT+ vehicle) and recovered to 1357.0 ± 87.8 and 1221.0 ± 96.8 after treatment with LASSBio-1386 and sildenafil, respectively. Pulmonary acceleration time (PAT) (ms) was reduced from 45.3 ± 0.8 (control) to 21.9 ± 0.3 in MCT + vehicle group ( P < 0.05) and restored to 42.9 ± 0.7 in MCT + LASSBio-1386 group, but it was only partially restored to 37.8 ± 1.3 (ms) in MCT + Sildenafil-treated group. RVSP (mmHg) was increased from 27.1 ± 0.7 (control) to 52.9 ± 1.5 in the PH rats and was reduced to 29.1 ± 1.0 and to 31.8 ± 0.6 after treatment with LASSBio-1386 and sildenafil. PH induced an increase of RV/BW (mg/g) from 0.62 ± 0.03 (control) to 1.81 ± 0.20 which was reduced to 0.70 ± 0.07 after administration of LASSBio-1386. Sildenafil treatment did not reverse the RV hypertrophy in PH rats (RV/BW = 1.52 ± 0.10 mg/g). Conclusions: LASSBio-1386 was effective to prevent RV dysfunction and exercise intolerance indicating important implications for ongoing clinical evaluation of multi-target drugs for the treatment of PAH.

ID: 9: AN IL7 MONOCLONAL ANTIBODY RESCUES HYPOXIA-MEDIATED PULMONARY HYPERTENSION IN MICE

2016 ◽  
Vol 64 (4) ◽  
pp. 921.3-922
Author(s):  
H Gao ◽  
Y Dong ◽  
RF Machado ◽  
J Chen
Keyword(s):  
Monoclonal Antibody ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Treated Group ◽  
Hypoxic Exposure ◽  
Ventricular Systolic Pressure ◽  
Hypoxia Exposure ◽  
Protein Levels

RationalePreviously we showed that human plasma IL7, protein levels of IL7 receptor (IL7R) in total lung homogenate and pulmonary artery endothelial cells (PAECs)/PASMCs were significantly elevated in PAH patients. IL7 promotes PASMC proliferation. IL7R-deficient (IL7R−/−) mice are protected from hypoxia-mediated pulmonary hypertension (HPH). We sought to study whether blocking IL7 via anti-IL7 antibodies can reverse experimental PH in mice.MethodsMale C57BL/6 mice (7 week old) were exposed to normoxia or hypoxia (10% O2) for 4 weeks (n=6 per group). At Day 12 after hypoxia exposure, a monoclonal antibody against IL7 (AB-407-na, R&D Systems) or control IgG was started to treat the mice (100 µg/mouse, every other day, IP, for two weeks). Right ventricular systolic pressure (RVSP) was determined with a Millar pressure transducer catheter. The right ventricle: left ventricle +septum (RV/LV+S) ratio was calculated. Pulmonary artery remodeling was assessed using Aperio image software.ResultAfter four weeks of hypoxic exposure, treatment of IL7 antibody significantly attenuated RVSP (28.89±0.87 vs. 34.43±2.23 mm Hg, p=0.03), developed less right ventricular hypertrophy (RVH) (RV/LV+S 0.29±0.0087 vs. 0.39±0.014, p=0.0002), and lower pulmonary arterial thickness when compared to control-IgG treated group.ConclusionIL7 antibodies reverse HPH in mice. IL7 antibodies could be a novel therapeutic candidate for pulmonary hypertension.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

2015 ◽  
Vol 309 (10) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Michiel Alexander de Raaf ◽  
Yvet Kroeze ◽  
Anthonieke Middelman ◽  
Frances S. de Man ◽  
Helma de Jong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Serotonin Transporter ◽  
Rat Model ◽  
Systolic Pressure ◽  
Serum Levels ◽  
Normal Function ◽  
Ventricular Systolic Pressure ◽  
Serotonin System ◽  
Pulmonary Arterial

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats

2002 ◽  
Vol 283 (5) ◽  
pp. H2021-H2028 ◽  
Author(s):  
Yasuhiro Ikeda ◽  
Yoshikazu Yonemitsu ◽  
Chu Kataoka ◽  
Shiro Kitamoto ◽  
Terutoshi Yamaoka ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Mononuclear Cells ◽  
Systolic Pressure ◽  
Signal Pathway ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Ventricular Systolic Pressure

Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in the initiation and/or progression of pulmonary hypertension (PH). To determine whether blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding a 7-NH2terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2-wk intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate whether a longer or higher expression might be more effective. The intramuscular reporter gene expression was enhanced 10 times over that by EP than by simple injection, and a significant 7ND MCP-1 protein in plasma was detected only in the EP group. 7ND MCP-1 gene transfer significantly inhibited the progression of MCT-induced PH as evaluated by right ventricular systolic pressure, right ventricular hypertrophy, medial hypertrophy of pulumonary arterioles, and mononuclear cell infiltration into the lung. Differential effects of longer or higher transgene expression were not apparent. Although the in vivo kinetics of 7ND MCP-1 gene therapy should be studied further, these encouraging results suggest that an anti-inflammatory strategy via blockade of the MCP-1 signal pathway may be an alternative approach to treat subjects with PH.

scholarly journals Chronic Hypoxia Decreases Endothelial Connexin 40, Attenuates Endothelium‐Dependent Hyperpolarization–Mediated Relaxation in Small Distal Pulmonary Arteries, and Leads to Pulmonary Hypertension

2020 ◽  
Vol 9 (24) ◽  
Author(s):  
Rui Si ◽  
Qian Zhang ◽  
Jody Tori O. Cabrera ◽  
Qiuyu Zheng ◽  
Atsumi Tsuji‐Hosokawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Knockout Mice ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelial Cells ◽  
Endothelium Dependent Relaxation

Background Abnormal endothelial function in the lungs is implicated in the development of pulmonary hypertension; however, there is little information about the difference of endothelial function between small distal pulmonary artery (PA) and large proximal PA and their contribution to the development of pulmonary hypertension. Herein, we investigate endothelium‐dependent relaxation in different orders of PAs and examine the molecular mechanisms by which chronic hypoxia attenuates endothelium‐dependent pulmonary vasodilation, leading to pulmonary hypertension. Methods and Results Endothelium‐dependent relaxation in large proximal PAs (second order) was primarily caused by releasing NO from the endothelium, whereas endothelium‐dependent hyperpolarization (EDH)–mediated vasodilation was prominent in small distal PAs (fourth–fifth order). Chronic hypoxia abolished EDH‐mediated relaxation in small distal PAs without affecting smooth muscle–dependent relaxation. RNA‐sequencing data revealed that, among genes related to EDH, the levels of Cx37 , Cx40 , Cx43 , and IK were altered in mouse pulmonary endothelial cells isolated from chronically hypoxic mice in comparison to mouse pulmonary endothelial cells from normoxic control mice. The protein levels were significantly lower for connexin 40 (Cx40) and higher for connexin 37 in mouse pulmonary endothelial cells from hypoxic mice than normoxic mice. Cx40 knockout mice exhibited significant attenuation of EDH‐mediated relaxation and marked increase in right ventricular systolic pressure. Interestingly, chronic hypoxia led to a further increase in right ventricular systolic pressure in Cx40 knockout mice without altering EDH‐mediated relaxation. Furthermore, overexpression of Cx40 significantly decreased right ventricular systolic pressure in chronically hypoxic mice. Conclusions These data suggest that chronic hypoxia‐induced downregulation of endothelial Cx40 results in impaired EDH‐mediated relaxation in small distal PAs and contributes to the development of pulmonary hypertension.

Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

1993 ◽  
Vol 75 (4) ◽  
pp. 1615-1623 ◽  
Author(s):  
J. R. Klinger ◽  
R. D. Petit ◽  
R. R. Warburton ◽  
D. S. Wrenn ◽  
F. Arnal ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Neutral Endopeptidase ◽  
Mrna Levels ◽  
Hypoxic Pulmonary Hypertension ◽  
Ventricular Systolic Pressure ◽  
Nep Inhibition

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

2014 ◽  
Vol 306 (1) ◽  
pp. H41-H52 ◽  
Author(s):  
Carlos H. Nitta ◽  
David A. Osmond ◽  
Lindsay M. Herbert ◽  
Britta F. Beasley ◽  
Thomas C. Resta ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Arterial Remodeling ◽  
Ventricular Systolic Pressure ◽  
Intracellular Ca

Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.

scholarly journals Functional impact of exercise pulmonary hypertension in patients with borderline resting pulmonary arterial pressure

2017 ◽  
Vol 7 (3) ◽  
pp. 654-665 ◽  
Author(s):  
Rudolf K. F. Oliveira ◽  
Mariana Faria-Urbina ◽  
Bradley A. Maron ◽  
Mario Santos ◽  
Aaron B. Waxman ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Oxygen Uptake ◽  
Arterial Pressure ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
Pulmonary Arterial Pressure ◽  
Peak Oxygen Uptake ◽  
Exercise Intolerance ◽  
Functional Impact ◽  
Pulmonary Arterial

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13–16, 17–20, and 21–24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13–16, 17–20, and 21–24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats

2021 ◽  
pp. 1-15
Author(s):  
Lars K. Markvardsen ◽  
Lene D. Sønderskov ◽  
Christine Wandall-Frostholm ◽  
Estéfano Pinilla ◽  
Judit Prat-Duran ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Lung Tissue ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
The Right

<b><i>Introduction:</i></b> Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. <b><i>Methods:</i></b> Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. <b><i>Results:</i></b> Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. <b><i>Discussion/Conclusions:</i></b> Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

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