scholarly journals EXPRESS: SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

2021 ◽  
pp. 204589402110215
Author(s):  
Ravikumar Sitapara ◽  
Chuluunbaatar Sugarragchaa ◽  
Lawrence Zisman
Keyword(s):  
Systolic Pressure ◽  
Binding Constants ◽  
Osmotic Pump ◽  
Pharmacokinetic Studies ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Vegfr Inhibitor ◽  
Normal Controls

Introduction: SU5416 plus chronic hypoxia causes pulmonary arterial hypertension (PAH) in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe PAH in rats. Methods: Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib SC or via osmotic pump and kept hypoxic for 3 weeks. Right ventricular systolic pressure (RVSP) and hypertrophy (RVH) were evaluated at day 14 and 28 following removal from hypoxia. RV fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Results: Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib SC plus hypoxia did not induce severe PAH. RVSP at 14 and 28d post-hypoxia was 36.8 ± 2.3 mmHg and 36.2 ± 3.4 mmHg, respectively, versus 27.5 ± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, RVSP was 40.0 ± 3.1 mmHg at 14d and 27.9 ± 1.9 mmHg at 28d post-hypoxia. SU5416 plus hypoxia induced severe PAH (RVSP 61.9 ± 6.1 mmHg and 64.9 ± 8.4 mmHg at 14d and 28d post-hypoxia, respectively). Cabozantinib induced less RVH (RV/(LV+IVS) at 14d post-hypoxia compared to SU5416. RV fibrosis was more extensive in the SU5416 groups compared to the Cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 day post hypoxia group. Conclusion: Selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe PAH. Severe PAH due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.

scholarly journals Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Takanori Watanabe ◽  
Mariko Ishikawa ◽  
Kohtaro Abe ◽  
Tomohito Ishikawa ◽  
Satomi Imakiire ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Increase ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

scholarly journals JNK2 regulates vascular remodeling in pulmonary hypertension

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401877815
Author(s):  
Mita Das ◽  
W. Michael Zawada ◽  
James West ◽  
Kurt R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Wall Thickening ◽  
Ventricular Systolic Pressure ◽  
Vascular Abnormalities ◽  
Map Kinase Phosphatase ◽  
Pulmonary Arterial ◽  
Jnk Isoforms

Pulmonary arterial (PA) wall modifications are key pathological features of pulmonary hypertension (PH). Although such abnormalities correlate with heightened phosphorylation of c-Jun N-terminal kinases 1/2 (JNK1/2) in a rat model of PH, the contribution of specific JNK isoforms to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA remodeling in PH. We detected increased JNK1/2 phosphorylation in the thickened vessels of PH patients’ lungs compared to that in lungs of healthy individuals. JNK1/2 phosphorylation paralleled a marked reduction in MAP kinase phosphatase 1 (JNK dephosphorylator) expression in patients’ lungs. Association of JNK1/2 activation with vascular modification was confirmed in the calf model of severe hypoxia-induced PH. To ascertain the role of each JNK isoform in pathophysiology of PH, wild-type (WT), JNK1 null (JNK1-/-), and JNK2 null (JNK2-/-) mice were exposed to chronic hypoxia (10% O2 for six weeks) to develop PH. In hypoxic WT lungs, an increase in JNK1/2 phosphorylation was associated with PH-like pathology. Hallmarks of PH pathophysiology, i.e. excessive accumulation of extracellular matrix and vessel muscularization with medial wall thickening, was also detected in hypoxic JNK1-/- lungs, but not in hypoxia-exposed JNK2-/- lungs. However, hypoxia-induced increases in right ventricular systolic pressure (RVSP) and in right ventricular hypertrophy (RVH) were similar in all three genotypes. Our findings suggest that JNK2 participates in PA remodeling (but likely not in vasoconstriction) in murine hypoxic PH and that modulating JNK2 actions might quell vascular abnormalities and limit the course of PH.

Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

2021 ◽  
pp. 2000653
Author(s):  
Hélène Le Ribeuz ◽  
Lucie To ◽  
Maria-Rosa Ghigna ◽  
Clémence Martin ◽  
Chandran Nagaraj ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Vascular Cell ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

IntroductionA reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.Aim and objectivesWe aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and resultsRT-Q-PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myograph on human, pig and rat PAs, we demonstrated that CFTR activation induces PAs relaxation. CFTR-mediated PA relaxation was reduced in PAs from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularization. Pathologic assessment of lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.ConclusionsCFTR expression is strongly decreased in PA smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces PA relaxation.

scholarly journals Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats

2014 ◽  
Vol 306 (2) ◽  
pp. H243-H250 ◽  
Author(s):  
Michie Toba ◽  
Abdallah Alzoubi ◽  
Kealan D. O'Neill ◽  
Salina Gairhe ◽  
Yuri Matsumoto ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Male Rats ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Time Points ◽  
Pulmonary Arterial ◽  
Time Point

We have investigated the temporal relationship between the hemodynamic and histological/morphological progression in a rat model of pulmonary arterial hypertension that develops pulmonary arterial lesions morphologically indistinguishable from those in human pulmonary arterial hypertension. Adult male rats were injected with Sugen5416 and exposed to hypoxia for 3 wk followed by a return to normoxia for various additional weeks. At 1, 3, 5, 8, and 13 wk after the Sugen5416 injection, hemodynamic and histological examinations were performed. Right ventricular systolic pressure reached its maximum 5 wk after Sugen5416 injection and plateaued thereafter. Cardiac index decreased at the 3∼5-wk time point, and tended to further decline at later time points. Reflecting these changes, calculated total pulmonary resistance showed a pattern of progressive worsening. Acute intravenous fasudil markedly reduced the elevated pressure and resistance at all time points tested. The percentage of severely occluded small pulmonary arteries showed a similar pattern of progression to that of right ventricular systolic pressure. These small vessels were occluded predominantly with nonplexiform-type neointimal formation except for the 13-wk time point. There was no severe occlusion in larger arteries until the 13-wk time point, when significant numbers of vessels were occluded with plexiform-type neointima. The Sugen5416/hypoxia/normoxia-exposed rat shows a pattern of chronic hemodynamic progression similar to that observed in pulmonary arterial hypertension patients. In addition to vasoconstriction, nonplexiform-type neointimal occlusion of small arteries appears to contribute significantly to the early phase of pulmonary arterial hypertension development, and plexiform-type larger vessel occlusion may play a role in the late deterioration.

scholarly journals The angiopietin-1–Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice

2009 ◽  
Vol 206 (10) ◽  
pp. 2221-2234 ◽  
Author(s):  
Lakshmi Kugathasan ◽  
Julie Basu Ray ◽  
Yupu Deng ◽  
Effat Rezaei ◽  
Daniel J. Dumont ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Transgenic Mice ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Endothelial Activation ◽  
Pulmonary Hemodynamics ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Deficient Mice

The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/−) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2+/− group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1–Tie2 pathway is protective in PAH.

scholarly journals Inhibition of HDAC1 alleviates monocrotaline-induced pulmonary arterial remodeling through up-regulation of miR-34a

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Fangwei Li ◽  
Dan Wang ◽  
Hong Wang ◽  
Lijun Chen ◽  
Xilu Sun ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Intraperitoneal Injection ◽  
Systolic Pressure ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Arterial Remodeling ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Ventricle Hypertrophy ◽  
Metalloproteinase 9

Abstract Background It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. Methods PAH rat models were induced by intraperitoneal injection of MCT. HDAC1 was suppressed by intraperitoneal injection of the class I HDAC inhibitor MS-275, and miR-34a was over-expressed via tail vein injection of miR-34a agomiR. Results HDAC1 protein was significantly increased in MCT-induced PAH rats; this was accompanied with down-regulation of miR-34a and subsequent up-regulation of matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2/TIMP-2. Administration of PAH rats with MS-275 or miR-34a agomiR dramatically abolished MCT-induced reduction of miR-34a and subsequent up-regulation of MMP-9/TIMP-1 and MMP-2/TIMP-2, finally reduced extracellular matrix (ECM) accumulation, pulmonary arterial remodeling, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) in PAH rats. Conclusions HDAC1 contributes to the development of MCT-induced rat PAH by suppressing miR-34a level and subsequently up-regulating the ratio of MMP-9/TIMP-1 and MMP-2/TIMP-2. Inhibition of HDAC1 alleviates pulmonary arterial remodeling and PAH through up-regulation of miR-34a level and subsequent reduction of MMP-9/TIMP-1 and MMP-2/TIMP-2, suggesting that inhibition of HDAC1 might have potential value in the management of PAH.

scholarly journals Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1787-1798
Author(s):  
Fangcheng Luo ◽  
Liangmiao Wu ◽  
Guoqing Xie ◽  
FangFang Gao ◽  
Zhixiang Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pulmonary Vascular Disease ◽  
Arterial Remodeling ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Dual Functional ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare, progressive pulmonary vascular disease with limited therapeutic options. Pulmonary circulation resistance, pulmonary vascular remodeling, and over-activated NMDARs (N-methyl-d-aspartate receptors) play vital roles in the pathogenesis of PAH. In the present study, we aimed to evaluate the efficacy and molecular mechanism of MN-08, a dual-functional memantine nitrate derivative, in experimental animal models of PAH. MN-08 showed a high degree of accumulation in the lungs and dilated pulmonary arterial rings ex vivo by releasing nitric oxide. MN-08 did not lower systemic blood pressure. MN-08 attenuated right ventricular systolic pressure and right ventricular hypertrophy, inhibited pulmonary arterial remodeling, alleviated glutamate-NMDARs dysregulation, and improved survival rates in monocrotaline-induced PAH rats. More importantly, the therapeutic benefit of MN-08 for PAH was greater than that of sildenafil. Moreover, MN-08 can reduce right ventricular systolic pressure in U46619-induced acute PAH rats. Mechanistically, MN-08 suppressed proliferation of pulmonary arterial smooth muscle cells exposed to human platelet-derived growth factor-BB by regulating the cell cycle and expression of NMDAR1, AKT (serine/threonine kinase Akt), and ERK (extracellular signal-regulated kinase) 1/2. In conclusion, our studies demonstrated that MN-08 may be a promising therapeutic agent for PAH.

Nerve growth factor receptor is involved in maintaining homeostasis of pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Goten ◽  
S Usui ◽  
O Inoue ◽  
H Okada ◽  
S Takashima ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Chronic Hypoxia ◽  
Systolic Pressure ◽  
Growth Factor Receptor ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
The Right

Abstract Introduction Pulmonary arterial hypertension (PAH), characterized by vascular remodeling, is still disease with poor prognosis although many pulmonary vasodilators have been developed, and new mechanism of treatment for PAH is desired. Nerve growth factor receptor (Ngfr) is known to relate to inflammatory reaction and repair process in the damaged tissue. We have reported that Ngfr is associated to vascular remodeling in patients with acute coronary syndrome. However, it is unclear how Ngfr is involved in the pathogenesis of PAH. Purpose In this study, we investigated whether Ngfr relate to pathophysiology in PAH. Methods We estimated the frequency of Ngfr positive cells (% Ngfr+) in peripheral blood mononuclear cells obtained from PAH and non-PAH patients using flowcytometric analysis. In PAH patients, the hemodynamic parameters such as mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and cardiac index (CI) were obtained by right heart catheterization, and evaluated for correlation with the % Ngfr+. Next, adult 8-week-old C57BL/6 (WT) mice and Ngfr knock out (KO) mice were exposed to chronic hypoxia (10% O2) or normoxia for 6 weeks. Then, mice were anesthetized and performed echocardiography and right heart catheterization. Then, mice were exsanguinated and blood sample was collected to evaluate the % Ngfr+ by flow cytometry. Right ventricular weight was measured and lung tissue was also collected for histological assessment and molecular pathway profiling. Results PAH (n=24) patients and non-PAH patients (n=17) were enrolled. The % Ngfr+ was significantly higher in PAH patients than that in non-PAH patients (0.056% versus 0.019%, p<0.0001). In PAH patients, the % Ngfr+ was correlated with severity of hemodynamic parameters such as mPAP (R=0.64 p<0.001), PVR (R=0.62 p<0.005), and CI (R=−0.48 p<0.05). In WT mice, chronic hypoxia significantly increased the right ventricular systolic pressure and induced vascular medial thickness and fibrosis around the pulmonary artery. Flow cytometry analysis revealed that the % Ngfr+ was significantly increased in the hypoxia compared to that in the normoxia. Under hypoxic conditions, the right ventricular systolic pressure was significantly increased in Ngfr KO mice compared to that in WT mice. In histological analysis, hypoxia-induced peripheral vascular fibrosis and medial thickness was more severe in Ngfr KO than that in WT mice. Conclusion Circulating Ngfr-positive cells are associated with severity of PAH in patients. In the hypoxia-induced PH model, gene deletion of Ngfr shows the progression of the pathogenesis of PAH. These results suggest that circulating Ngfr-positive cells have an important role in the pathogenesis of PAH and may be a novel target for PAH therapy. Funding Acknowledgement Type of funding source: None

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