scholarly journals Superoxide Dismutase Mimetic, MnTE-2-PyP, Attenuates Chronic Hypoxia-Induced Pulmonary Hypertension, Pulmonary Vascular Remodeling, and Activation of the NALP3 Inflammasome

2013 ◽  
Vol 18 (14) ◽  
pp. 1753-1764 ◽  
Author(s):  
Leah R. Villegas ◽  
Dylan Kluck ◽  
Carlie Field ◽  
Rebecca E. Oberley-Deegan ◽  
Crystal Woods ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Superoxide Dismutase ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Vascular Remodeling ◽  
Nalp3 Inflammasome

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

2006 ◽  
Vol 291 (5) ◽  
pp. L912-L922 ◽  
Author(s):  
Crystal Kantores ◽  
Patrick J. McNamara ◽  
Lilian Teixeira ◽  
Doreen Engelberts ◽  
Prashanth Murthy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Antioxidant Properties ◽  
Ventricular Performance ◽  
Pulmonary Vascular Remodeling ◽  
Beneficial Effects ◽  
Arterial Resistance ◽  
Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

1997 ◽  
Vol 83 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Gene L. Colice ◽  
Nicholas Hill ◽  
Yan-Jie Lee ◽  
Hongkai Du ◽  
James Klinger ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Single Dose ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Minute Ventilation ◽  
Chronic Mountain Sickness ◽  
Pulmonary Vascular Remodeling ◽  
Increased Sensitivity ◽  
Pulmonary Arterial ◽  
Mountain Sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du, James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness. J. Appl. Physiol. 83(1): 25–31, 1997.—Hilltop (H) strain Sprague-Dawley rats are more susceptible to chronic mountain sickness than are the Madison (M) strain rats. It is unclear what role pulmonary vascular remodeling, polycythemia, and hypoxia-induced vasoconstriction play in mediating the more severe pulmonary hypertension that develops in the H rats during chronic hypoxia. It is also unclear whether the increased sensitivity of the H rats to chronic mountain sickness is specific for a hypoxia effect or, instead, reflects a general propensity toward the development of pulmonary hypertension. Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonary hypertension. We hypothesized that the difference in the pulmonary vascular response to chronic hypoxia between H and M rats reflects an increased sensitivity of the H rats to any pulmonary hypertensive stimuli. Consequently, we expected the two strains to also differ in their susceptibility to MCT-induced pulmonary hypertension. Pulmonary arterial pressures in conscious H and M rats were measured 3 wk after a single dose of MCT, exposure to a simulated high altitude of 18,000 ft (barometric pressure = 380 mmHg), and administration of a single dose of saline as a placebo. The H rats had significantly higher pulmonary arterial pressures and right ventricular weights after MCT and chronic hypoxia than did the M rats. The H rats also had more pulmonary vascular remodeling, i.e., greater wall thickness as a percentage of vessel diameter, after MCT and chronic hypoxia than did the M rats. The H rats had significantly lower arterial[Formula: see text] than did the M rats after MCT, but the degree of hypoxemia was mild [arterial[Formula: see text] of 72.5 ± 0.8 (SE) Torr for H rats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H rats had lower arterial [Formula: see text] and larger minute ventilation values than did the M rats after MCT. These ventilatory differences suggest that MCT caused more severe pulmonary vascular damage in the H rats than in the M rats. These data support the hypothesis that the H rats have a general propensity to develop pulmonary hypertension and suggest that differences in pulmonary vascular remodeling account for the increased susceptibility of H rats, compared with M rats, to both MCT and chronic hypoxia-induced pulmonary hypertension.

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats

1992 ◽  
Vol 73 (3) ◽  
pp. 1084-1092 ◽  
Author(s):  
S. Ono ◽  
J. Y. Westcott ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Paf Antagonists ◽  
Isolated Lungs

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

2009 ◽  
Vol 297 (4) ◽  
pp. L658-L665 ◽  
Author(s):  
Norbert Weissmann ◽  
Sascha Hackemack ◽  
Bhola Kumar Dahal ◽  
Soni Savai Pullamsetti ◽  
Rajkumar Savai ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Soluble Guanylate Cyclase ◽  
Pressor Response ◽  
Acute Hypoxia ◽  
Heart Hypertrophy ◽  
Right Heart ◽  
Pulmonary Vascular Remodeling

Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg·kg−1·day−1), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.

scholarly journals HIF and pulmonary vascular responses to hypoxia

2014 ◽  
Vol 116 (7) ◽  
pp. 867-874 ◽  
Author(s):  
Larissa A. Shimoda ◽  
Steven S. Laurie
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Human Subjects ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factors ◽  
Pulmonary Vascular Remodeling ◽  
Vascular Responses ◽  
Pulmonary Vasoconstriction ◽  
Oxygen Sensitive

In the lung, acute reductions in oxygen lead to hypoxic pulmonary vasoconstriction, whereas prolonged exposures to hypoxia result in sustained vasoconstriction, pulmonary vascular remodeling, and the development of pulmonary hypertension. Data from both human subjects and animal models implicate a role for hypoxia-inducible factors (HIFs), oxygen-sensitive transcription factors, in pulmonary vascular responses to both acute and chronic hypoxia. In this review, we discuss work from our laboratory and others supporting a role for HIF in modulating hypoxic pulmonary vasoconstriction and mediating hypoxia-induced pulmonary hypertension, identify some of the downstream targets of HIF, and assess the potential to pharmacologically target the HIF system.

scholarly journals 2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

PRILOZI ◽  
2021 ◽  
Vol 42 (1) ◽  
pp. 41-51
Author(s):  
Stevan P. Tofovic ◽  
Xinchen Zhang ◽  
Tom J. Jones ◽  
Gordana Petruševska
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Pleural Effusion ◽  
Lung Injury ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Biological Effects ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling

Abstract Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

scholarly journals Eplerenone Improves Pulmonary Vascular Remodeling and Hypertension by Inhibition of the Mineralocorticoid Receptor in Endothelial Cells

Hypertension ◽  
2021 ◽  
Author(s):  
Jessica Kowalski ◽  
Lisa Deng ◽  
Chiara Suennen ◽  
Duygu Koca ◽  
David Meral ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Remodeling ◽  
Mineralocorticoid Receptor ◽  
Chronic Hypoxia ◽  
Cell Type ◽  
Pulmonary Vascular Remodeling ◽  
Cell Type Specific

Pulmonary hypertension is characterized by progressive remodeling of the pulmonary arteries, however, this is not therapeutically targeted yet. Aldosterone and the MR (mineralocorticoid receptor) are key drivers of cardiovascular disease, and there is a growing body of evidence suggesting a role in pulmonary hypertension. Thus, the aim of this study was to investigate the impact of cell type-specific deletion of MR on pulmonary vascular remodeling. To induce pulmonary hypertension, mice were exposed to chronic hypoxia for 6 weeks. Treatment with the MR antagonist eplerenone attenuated pulmonary vascular remodeling, hypertension, and right ventricular dysfunction. In contrast, aldosterone infusion via osmotic minipumps induced pulmonary vascular remodeling. We created 4 different mouse models with cell type-specific MR deletion in smooth muscle cells, endothelial cells, macrophages, or fibroblasts and exposed them to chronic hypoxia. MR deletion from endothelial cells fully recapitulated the beneficial effects of eplerenone while MR deletion from other cell types had no detectable effect on pulmonary vascular remodeling. RNA-seq from isolated MR-deficient and wildtype pulmonary endothelial cells revealed differentially expressed genes as potential downstream mediators of MR related to pulmonary hypertension, including genes related to the endothelin signaling pathway. MR antagonists improve hypoxia-induced pulmonary vascular remodeling via inhibition of MR in endothelial cells but independent from MR in smooth muscle cells, fibroblasts, or macrophages. The results from this study provide the basis for future investigation of potential downstream mediators of MR involved in pulmonary hypertension and further support the clinical evaluation of MR antagonists in pulmonary hypertension.

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.

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