scholarly journals CTRP9 Mitigates the Progression of Arteriovenous Shunt-Induced Pulmonary Artery Hypertension in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Hua Guan ◽  
Xiaofeng Yang ◽  
Tao Shi ◽  
Yongjian Zhang ◽  
Aoqi Xiang ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Systolic Pressure ◽  
Pulmonary Artery Hypertension ◽  
Arteriovenous Shunt ◽  
Ventricular Systolic Pressure ◽  
Vascular Homeostasis ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
New Perspective ◽  
Green Fluorescent

The present study is aimed at investigating the molecular mechanism of C1q/TNF-related protein 9 (CTRP9) and providing a new perspective in arteriovenous shunt-induced pulmonary arterial hypertension (PAH). PAH was established by an arteriovenous shunt placement performed in rats. Adenovirus(Ad)-CTRP9 and Ad-green fluorescent protein viral particles were injected into the rats through the tail vein. Following 12 weeks, the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured and morphological analysis was conducted to confirm the establishment of the PAH model. The systemic elevation of CTRP9 maintained pulmonary vascular homeostasis and protected the rats from dysfunctional and abnormal remodeling. CTRP9 attenuated the pulmonary vascular remodeling in the shunt group by decreasing the mPAP and RVSP, which was associated with suppressed inflammation, apoptosis, and extracellular matrix injury. In addition, CTRP9 dramatically increased the phosphorylation of AKT and p38-MAPK in the lung tissues of shunt-operated animals. These findings suggest a previously unrecognized effect of CTRP9 in pulmonary vascular homeostasis during PAH pathogenesis.

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.

Effects of Crocin on CCL2/CCR2 Inflammatory Pathway in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats

2021 ◽  
pp. 1-19
Author(s):  
Yanling Sheng ◽  
Xiaowei Gong ◽  
Jing Zhao ◽  
Yan Liu ◽  
Yadong Yuan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Stress Responses ◽  
Systolic Pressure ◽  
Pathological Feature ◽  
Arterial Remodeling ◽  
Inflammatory Pathway ◽  
Ventricular Systolic Pressure ◽  
Rat Models ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a malignant cardiopulmonary disease, in which pulmonary arterial remodeling is regarded as the prominent pathological feature. So far, the mechanism of PAH is still unclear, so its treatment remains a challenge. However, inflammation plays an important part in the occurrence and progression of PAH. It is well known that crocin has anti-inflammatory properties, so we investigated whether crocin could be a potential drug for the treatment of PAH rat models. Rats injected subcutaneously with monocrotaline (MCT) were treated with crocin via a gastric tube daily for four weeks. The results showed that crocin treatment significantly reduced the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) in the PAH rat models. Moreover, crocin treatment reduced the proliferation of pulmonary arteriole smooth muscle cells (PASMCs). In addition, crocin treatment not only relieved inflammatory cell infiltration and collagen fiber hyperplasia in the lung and right ventricle, but also decreased the expression of the CCL2/CCR2 inflammatory pathway in the lung of PAH rat models. Furthermore, crocin treatment reduced the inflammatory cytokines and oxidative stress responses. In summary, crocin may play a protective role in MCT-induced PAH rats by alleviating inflammatory response, improving pulmonary arterial remodeling, and preventing PAH. Therefore, crocin as a new treatment for PAH may be quite worthy of consideration.

Abstract 17213: Crizotinib Exacerbates the Severity of Pah in a Preclinical Rat Model

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Francois Potus ◽  
Boucherat Olivier ◽  
Provencher Steeve ◽  
Bonnet Sébastien
Keyword(s):  
Right Ventricular ◽  
Small Cell Lung Carcinoma ◽  
Pulmonary Arteries ◽  
Systolic Pressure ◽  
Chemotherapeutic Agents ◽  
Pulmonary Vasculature ◽  
Drug Induced ◽  
Cell Lung Carcinoma ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Introduction: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy histologically associated with remodeling of distal pulmonary arteries and right ventricular failure that is drug-induced in approximately 10% of cases. Recently, PAH induced by chemotherapeutic agents such as RTK inhibitors (e.g. dasatinib) has been described. Crizotinib is a new MET inhibitor increasingly used for the treatment of ALK-positive non-small cell lung carcinoma. Interestingly, crizotinib has been shown to induce endothelial cells (EC) dysfunction (e.g. inhibition of EC survival and angiogenesis) and is symptomatically associated with dyspnea and peripheral oedema in many patients, which are cardinal symptoms of PAH. We thus hypothesized that chronic administration of crizotinib exacerbates PAH. Material and results: We observed a significant increase of mortality rate in PAH rats (Sugen/hypoxia model) treated with daily oral administration of crizotinib (100mg/kg/d for 2 weeks) compared to rats treated with vehicle (6/group; p<0.05). Furthermore, we demonstrated that crizotinib treatment was associated with increases in right ventricular systolic pressure, mean pulmonary arterial pressure and pulmonary vasculature resistance; and decreases in cardiac output and stroke volume (right heart catheterizations in closed chest) compared to vehicle-treated rats with Sugen-induced PAH (4 PAH+crizotinib; 6 PAH+vehicle, 5 PAH and 3 control rats; p<0.05). Histologically, crizotinib administration significantly increased pulmonary arteries wall thickness as well as right ventricular fibrosis (p<0.05). Finally, crizotinib increased macrophage accumulation and size within the lungs of PAH rats (p<0.05). Conclusion: We documented for the first time that crizotinib treatment markedly increases vascular remodeling and macrophage activation with concomitantly marked PAH exacerbation in Sugen rats. This study could have major clinical relevance in the management of patients treated with crizotinib.

scholarly journals Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis

2015 ◽  
Vol 308 (6) ◽  
pp. L523-L538 ◽  
Author(s):  
Tsutomu Shinohara ◽  
Hirofumi Sawada ◽  
Shoichiro Otsuki ◽  
Noriko Yodoya ◽  
Taichi Kato ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Survivin Expression ◽  
Pulmonary Vascular Disease ◽  
Ventricular Systolic Pressure ◽  
Targeting Therapy ◽  
Pulmonary Arterial ◽  
Medial Wall Thickness ◽  
Endothelial Growth Factor

It remains unknown whether current disease-targeting therapy can histologically reverse obstructive pulmonary vasculopathy and how the timing of the therapy influences the antiremodeling effects of the compound. We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. Rats with pulmonary arterial hypertension (PAH), which were produced by combined exposure to a vascular endothelial growth factor receptor inhibitor Sugen 5416 and hypobaric hypoxia for 3 wk, were assigned to receive macitentan or vehicle during 3–5 wk (early study) or during 5–8 wk (late study) after Sugen injection. Compared with vehicle-treated PAH rats and PAH rats evaluated before treatment initiation, the macitentan-treated rats showed decreases in the proportion of occlusive lesions in the early study, a finding consistent with the reversal of right ventricular systolic pressure and indexes of right ventricular hypertrophy and medial wall thickness. Macitentan ameliorated but did not reverse the proportion of occlusive lesions in the late study. Although macitentan decreased the proportion of Ki67+ lesions in both studies, macitentan increased the proportion of cleaved caspase 3+ lesions and suppressed an antiapoptotic molecule survivin expression in the early study but not in the late study. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.

scholarly journals Preoperative 2D-echocardiographic assessment of pulmonary arterial pressure in subgroups of liver transplantation recipients

2021 ◽  
Vol 16 (4) ◽  
pp. 344-352
Author(s):  
Jungchan Park ◽  
Myung Soo Park ◽  
Ji-Hye Kwon ◽  
Ah Ran Oh ◽  
Seung-Hwa Lee ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Systolic Pressure ◽  
Heart Catheterization ◽  
Predictive Values ◽  
Ventricular Systolic Pressure ◽  
2D Echocardiography ◽  
Echocardiographic Assessment ◽  
Pulmonary Arterial

Background: The clinical efficacy of preoperative 2D-echocardiographic assessment of pulmonary arterial pressure (PAP) has not been evaluated fully in liver transplantation (LT) recipients.Methods: From October 2010 to February 2017, a total of 344 LT recipients who underwent preoperative 2D-echocardiography and intraoperative right heart catheterization (RHC) was enrolled and stratified according to etiology, disease progression, and clinical setting. The correlation of right ventricular systolic pressure (RVSP) on preoperative 2D-echocardiography with mean and systolic PAP on intraoperative RHC was evaluated, and the predictive value of RVSP > 50 mmHg to identify mean PAP > 35 mmHg was estimated.Results: In the overall population, significant but weak correlations were observed (R = 0.27; P < 0.001 for systolic PAP, R = 0.24; P < 0.001 for mean PAP). The positive and negative predictive values of RVSP > 50 mmHg identifying mean PAP > 35 mmHg were 37.5% and 49.9%, respectively. In the subgroup analyses, correlations were not significant in recipients of deceased donor type LT (R = 0.129; P = 0.224 for systolic PAP, R = 0.163; P = 0.126 for mean PAP) or in recipients with poorly controlled ascites (R = 0.215; P = 0.072 for systolic PAP, R = 0.21; P = 0.079 for mean PAP). Conclusion: In LT recipients, the correlation between RVSP on preoperative 2D-echocardiography and PAP on intraoperative RHC was weak; thus, preoperative 2D-echocardiography might not be the optimal tool for predicting intraoperative PAP. In LT candidates at risk of pulmonary hypertension, RHC should be considered.

scholarly journals Echocardiographic parameters related to pulmonary arterial hypertension in patients with chronic myeloid leukemia under dasatinib treatment

2021 ◽  
Vol 21 (4) ◽  
pp. 682-691
Author(s):  
Karla Poot Noh ◽  
Ernesto Hernández Jiménez ◽  
María del Rayo Juárez Santiesteban ◽  
Patricia Zaqoya Martínez ◽  
Alvaro J. Monliel Jarquin ◽  
...  
Keyword(s):  
Treatment Time ◽  
Pearson Correlation ◽  
Systolic Pressure ◽  
Pulmonary Artery Systolic Pressure ◽  
Cross Sectional ◽  
Mean Pulmonary Arterial Pressure ◽  
Ventricular Diastolic Dysfunction ◽  
Echocardiographic Parameters ◽  
Pulmonary Arterial

Introduction: The use of dasatinib in patients with CML has improved life expectancy and follow-up with transthoracic echocardiography (ECOTT) for early detection of PAH allows modifications to the treatment. Objective: To determine the echocardiographic parameters and echocardiographic probability for PAH in patients with CML treated with dasatinib. Methods: Correlation, cross-sectional, retrospective, single-center study; patients with CML treated with dasatinib were included. Spearman and Pearson correlation was used. Results: 16 patients were analyzed, mean age 53.5 years; 62.5% men, 37.5% women. The dasatinib dose was 50 mg / day in 18.7%, and 100 mg / day in 81.2%, mean pulmonary arterial pressure (mPAP) 26.3 mmHg, mean maximum tricuspid regurgitation velocity (VmxRT) 2.9 m / s, mean pulmonary artery systolic pressure (PSAP) 41 mmHg. 56.2% had right ventricular diastolic dysfunction (RVDD). 43% were categorized as low probability for PAH, 18.7% intermediate, and 37.5% as high. Relationship between PAPm and VmxRT with p = 0.012. Relationship between mPAP and RV diastolic function, with p = 0.002. Relationship between probability for PAH and mPAP, with p = 0.008. Conclusion: The echocardiographic parameters PAPm, VmxRT, PSAP, DDVD and echocardiographic probability for PAH are useful and necessary for the diagnosis of PAH. The determination of all these parameters should be carried out early and as a follow-up, since a considerable positive relationship was found for each one with the presence of PAH, which is not dependent on the treatment time or the dose of dasatinib.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

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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