Evidence that hypoxic pulmonary vascular remodeling in rats is polyamine dependent

1987 ◽  
Vol 62 (4) ◽  
pp. 1562-1568 ◽  
Author(s):  
J. E. Atkinson ◽  
J. W. Olson ◽  
R. J. Altiere ◽  
M. N. Gillespie
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Right Ventricular Hypertrophy ◽  
Polyamine Biosynthesis ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

This study tested the hypothesis that the polyamines, a family of low-molecular-weight organic cations with documented regulatory roles in cell growth and differentiation, are mediators of chronic hypoxia-induced pulmonary vascular remodeling. Relative to room air controls, chronically hypoxic animals (inspired O2 fraction = 0.1; 21 days) exhibited higher pulmonary arterial pressures (measured in room air), thicker medial layers in pulmonary arteries of 50–100 microns diam, increased hematocrits, and right ventricular hypertrophy. In addition, lung contents of the polyamines, putrescine, spermidine, and spermine were greater in hypoxic animals than in controls. alpha-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, attenuated the hypoxia-induced elevations in lung putrescine and spermidine content and blunted the increases in pulmonary arterial pressure and medial thickness. Neither the increased hematocrit nor right ventricular hypertrophy associated with chronic hypoxia were abrogated by DFMO. In addition, DFMO failed to influence vasoconstrictor responses provoked by acute hypoxic ventilation in isolated, buffer-perfused rat lungs. These observations suggest that depression of polyamine biosynthesis with DFMO blunts the sustained increase in pulmonary arterial pressure by attenuating hypoxia-induced medial thickening.

Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling

2000 ◽  
Vol 278 (2) ◽  
pp. H331-H338 ◽  
Author(s):  
Henry Ooi ◽  
Elaine Cadogan ◽  
Michèle Sweeney ◽  
Katherine Howell ◽  
R. G. O'Regan ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O2 fraction ([Formula: see text]) = 0.10], chronic hypercapnia (inspiratory CO2 fraction = 0.10), hypoxia-hypercapnia ([Formula: see text]= 0.10, inspiratory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone ( P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk ( P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 ± 1.8 mmHg) was significantly ( P < 0.01, ANOVA) elevated compared with control conditions (12.1 ± 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 ± 0.9 mmHg) or hypercapnia (11.8 ± 1.3 mmHg). HPV ([Formula: see text] = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control ( P < 0.05, ANOVA). Addition of N ω-nitro-l-arginine methyl ester (10−4 M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.

E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats

1999 ◽  
Vol 277 (2) ◽  
pp. L225-L232 ◽  
Author(s):  
Norihisa Hanasato ◽  
Masahiko Oka ◽  
Masashi Muramatsu ◽  
Mayu Nishino ◽  
Hideyuki Adachi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Output ◽  
Arterial Pressure ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Systemic Arterial Pressure ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Arterial

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Abstract 12535: MicroRNA-663 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension by Targeting TGFβ1/smad2/3 Signaling

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ni Zhu ◽  
Pan Li ◽  
He Du ◽  
Yongwen Qin ◽  
Xianxian Zhao
Keyword(s):  
Growth Factor ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Tgf Β1

Objective: Pulmonary vascular remodeling due to excessive growth factor production and pulmonary artery smooth muscle cells (PASMCs) proliferation is the hallmark feature of pulmonary arterial hypertension (PAH). Recent studies suggest that miR-663 is a potent modulator for tumorigenesis and atherosclerosis. However, whether miR-663 involves in pulmonary vascular remodeling is still unclear. Methods and Results: By using quantitative RT-PCR, we found that miR-663 was highly expressed in normal human PASMCs. In contrast, circulating level of miR-663 dramatically reduced in PAH patients. In addition, in situ hybridization showed that expression of miR-663 was decreased in PAMSCs of PAH patients. Furthermore, MTT and cell scratch-wound assay showed that transfection of miR-663 mimics significantly inhibited platelet derived growth factor (PDGF)-induced PASMC proliferation and migration, while knockdown of miR-663 expression enhanced these effects. Mechanistically, dual-luciferase reporter assay revealed that miR-663 directly targets the 3’UTR of TGF-β1. Moreover, western blots and ELISA results showed that miR-663 decreased PDGF-induced TGF-β1 expression and secretion, which in turn suppressed the downstream smad2/3 phosphorylation and collagen I expression. Finally, intratracheal instillation of adeno-miR-663 dramatically attenuated pulmonary vascular remodeling and right ventricular hypertrophy, as well as right ventricular systolic pressure and mean pulmonary arterial pressure in MCT-induced PAH rat models. Conclusion: These results indicate that miR-663 is a potential biomarker for PAH. MiR-663 decreases PDGF-BB-induced PAMSCs proliferation and ameliorates pulmonary vascular remodeling and right ventricular hypertrophy in MCT-PAH by targeting TGF-β1/smad2/3 signaling. These findings suggest that miR-663 may represent as an attractive approach for the diagnosis and treatment of PAH.

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat

1995 ◽  
Vol 269 (5) ◽  
pp. L690-L697 ◽  
Author(s):  
V. S. DiCarlo ◽  
S. J. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
M. Yano ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

Abstract 196: DDAH1 Knockout Exacerbates Hypoxia-induced Pulmonary Arterial Hypertension In Mice

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Dongmin Kwak ◽  
Dachun Xu ◽  
Dorothee Atzler ◽  
Xinli Hu ◽  
Xin Xu ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Gene Deletion ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Wild Type ◽  
Pulmonary Arterial ◽  
Nos Inhibitor ◽  
Deficient Mice

Pulmonary arterial hypertension (PAH) is a progressive disease with a very poor prognosis. Recent studies have demonstrated that PAH is associated with diminished nitric oxide bioavailability, increased levels of endogenous nitric oxide synthase (NOS) inhibitor ADMA, and decreased lung dimethylarginine dimethylaminohydrolase (DDAH) activity. We have demonstrated that DDAH1 is essential for degradation of endogenous NOS inhibitor ADMA, and is important for optimal vascular endothelial NO production. However, it is not clear whether decreased DDAH activity and ADMA accumulation exacerbates development or progression of PAH and right ventricular hypertrophy. In addition, the impact of cardiomyocyte specific DDAH1 dysfunction on right ventricular hypertrophy is unknown. Using global DDAH1 gene deficient mice, we demonstrate that chronic ADMA accumulation by global DDAH1 gene deletion did not cause spontaneous PAH under control conditions, but significantly exacerbated chronic hypoxia-induced PAH, as indicated by significantly increased right ventricular (RV) pressure, more RV hypertrophy, and enhanced pulmonary vascular remodeling in DDAH1 deficient mice as compared to wild type mice. Chronic hypoxia resulted in reduced lung DDAH activity and increased circulating ADMA content in wild type mice. Cardiomyocyte specific DDAH1 gene deletion did not exacerbate hypoxia-induced increases in RV pressure or lung vascular remodeling, but significantly exacerbated hypoxia-induced RV hypertrophy in comparison to wild type littermates, indicating DDAH1 distributed in cardiomyocytes protect the heart against RV hypertrophy independent to pressure overload. Collectively, our data indicate that lung DDAH1 plays a critical role in protection against hypoxia-induced PAH and right ventricular hypertrophy.

Mechanisms of lung polyamine accumulation in chronic hypoxic pulmonary hypertension

1990 ◽  
Vol 259 (6) ◽  
pp. L351-L358 ◽  
Author(s):  
R. T. Shiao ◽  
H. B. Kostenbauder ◽  
J. W. Olson ◽  
M. N. Gillespie
Keyword(s):  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Exposure ◽  
Maximal Velocity ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Environment ◽  
Elevated Activity ◽  
Pulmonary Arterial ◽  
Rate Limiting

Chronic hypoxia causes polyamine-dependent hypertensive pulmonary vascular remodeling (J. E. Atkinson. J. W. Olson, R. J. Altierre, and M. N. Gillespie, J. Appl. Physiol. 62: 1562–1568, 1987), but mechanisms by which lung polyamine contents are elevated have not been established. This study measured polyamine contents, biosynthetic activities, and transport in lungs of rats exposed to hypobaric hypoxia (simulated altitude: 4,570 m) for 4–14 days. Hypoxia increased lung contents of spermidine and spermine within 40 h and of putrescine within 4 days. These changes preceded hypoxia-induced increases in pulmonary arterial pressure and development of right ventricular hypertrophy. Additional experiments determined whether increased lung polyamine contents could be ascribed to elevated activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in conversion of ornithine to putrescine. Lung ODC activity did not differ from controls at 40 h posthypoxia and was reduced below control levels from 4–14 days of exposure. Putrescine transport kinetics were assessed in isolated, salt solution-perfused lungs. Apparent Km for putrescine uptake was increased from 10.4 microM in control lungs to 16.9 microM in lungs from rats maintained for 7 days in an hypoxic environment. Maximal velocity (Vmax) of lung putrescine transport was increased from 1.67 nmol.g-1.min-1 in controls to 2.65 in hypoxic lungs. Putrescine efflux also was altered by hypoxic exposure; T1/2 for loss of diamine from a slowly effluxing pool was increased from 60.6 min in controls to 91.5 min in hypoxic lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

2007 ◽  
Vol 8 (1) ◽  
Author(s):  
Renate Paddenberg ◽  
Philipp Stieger ◽  
Anna-Laura von Lilien ◽  
Petra Faulhammer ◽  
Anna Goldenberg ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling
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