Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension

Mathew, Rajamma; Gloster, Elizabeth S.; Sundararajan, T.; Thompson, Carl I.; Zeballos, Guillermo A.; Gewitz, Michael H.

doi:10.1152/jappl.1997.82.5.1493

Cited by 36 publications

(18 citation statements)

References 32 publications

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“…In both the MCT-alone and null-transfected animals, exuberant hypertrophy of the media of small muscular arteries and arterioles, as well as increased muscularity of the terminal arterioles, was apparent. As in previous reports using the MCT model, 16,17 morphometric analysis of the pulmonary tissue sections revealed that MCT significantly increased the medial area of small muscular arteries and arterioles compared with rats that were not treated with the pulmonary endothelial toxin (Figure 4). Medial area in the MCT-alone group was not different from the group receiving MCT together with pcDNA 3.1-transfected cells.…”

Section: Mct Experimentssupporting

confidence: 81%

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

et al. 2001

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Background-Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung. Methods and Results-We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy. Conclusions-These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.

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Section: Mct Experimentssupporting

confidence: 81%

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

et al. 2001

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“…In this context, it is important to note that most forms of PAH including MCT-induced PAH show a significant reduction in NO bioavailability. Treatment with exogenous NO not only attenuates PAH and RVH in the MCT model, but also preserves the expression of caveolin-1 protein (31,35). Since NO has an anti-inflammatory role, one of the mechanisms by which NO attenuates MCT-induced PAH may be via inhibition of inflammation and stabilization of endothelial plasmalemmal membrane resulting in the rescue of caveolin-1.…”

Section: Discussionmentioning

confidence: 99%

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Huang

Kaminski²,

Edwards³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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R. Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 294: L1250-L1259, 2008. First published April 4, 2008 doi:10.1152/ajplung.00069.2007.-Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) in rats is preceded by an inflammatory response, progressive endothelial cell membrane disruption, reduction in the expression of caveolin-1, and reciprocal activation of STAT3 (PY-STAT3). Superoxide and NF-B have been implicated in PAH. To evaluate the role of caveolin-1, PY-STAT3 activation, and superoxide in PAH, MCT-injected rats were treated daily with pyrrolidine dithiocarbamate (PDTC; starting on days 1, 3, and 14 ϫ 2 wk), an inhibitor of inflammation and NF-B activation. Hemodynamic data, the expression of inhibitory (I)-B␣, caveolin-1, and Tie2 (a membrane protein), activation of PY-STAT3 and NF-B, and superoxide chemiluminescence were examined. Rats developed progressive PAH at 2 wk post-MCT. There was progressive reduction in the expression of caveolin-1, Tie2, and activation of PY-STAT3 in the lungs. Reduction in I-B␣ expression was present at 2 and 4 wk post-MCT. Superoxide chemiluminescence and NF-B activation were observed only at 2 wk post-MCT and both decreased by 4 wk post-MCT despite progressive PAH. PDTC (starting on days 1 and 3) rescued caveolin-1 and Tie2, reversed MCT-induced PY-STAT3 activation, and attenuated PAH. In addition, PDTC restored I-B␣ expression and reduced superoxide chemiluminescence at 2 wk but did not inhibit NF-B activation despite attenuation of PAH. PDTC had no effect on established PAH. Increased superoxide chemiluminescence and NF-B activation appear to be a transient phenomenon in the MCT model. Thus the disruption of endothelial cell membrane integrity resulting in caveolin-1 loss and reciprocal activation of PY-STAT3 plays a key role in the MCT-induced PAH.caveolin-1; inhibitory B␣; inflammation; PY-STAT3; Tie2 DESPITE MAJOR ADVANCES MADE in the understanding of the pathogenesis of pulmonary artery hypertension (PAH), the precise molecular mechanism remains elusive. Both inflammation and oxidant stress have been implicated in the pathogenesis of PAH. Perivascular infiltration with inflammatory cells is evident in plexiform lesions in the lungs of patients with primary PAH, and the levels of proinflammatory cytokines such as IL-1 and IL-6 are elevated in the serum (22,47). In addition, the occurrence of PAH in patients suffering from systemic inflammatory diseases is not uncommon (14). Monocrotaline (MCT)-induced PAH in rats is preceded by an inflammatory response in the lungs and is associated with an early and progressive increase in the expression of IL-6 mRNA and IL-6 bioactivity in the lungs (6). IL-6 is known to activate STAT3, a transcription factor that positively regulates cell growth and proliferation. Tyrosine phosphorylation of STAT3 is required for STAT3 dimerization and subsequent translocation to nucleus where it binds with D...

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“…Lakes, NJ, USA) was inserted into the right carotid artery and connected to a pressure transducer (TP-300T; Nihon Kohden Co., Tokyo) for measurement of arterial blood pressure (BP). A 22G hypodermic needle was inserted into RV and a catheter (catheter-type transducer) (FT111B; Scisence, Inc., Ontario, Canada) was passed through the lumen of RV into the pulmonary artery to measure pulmonary arterial pressure (PAP) (35,36). Then RV pressure (RVP) was measured after the tip of the catheter was returned toward the RV.…”

Section: Animalsmentioning

confidence: 99%

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Sawamura

Kato²,

Fujita³

et al. 2009

J Pharmacol Sci

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Abstract. The aim of this study was to assess the effect of tadalafil (0.5, 2.5, and 10 mg /kg per day) on the progression of pulmonary arterial hypertension (PAH) in early treatment and on the survival rate in late treatment on the monocrotaline (MCT)-induced PAH rat model. Tadalafil was administered once daily to rats for 3 weeks from the day of MCT-injection or 21 days after the injection. With early treatment, tadalafil at 10 mg/kg per day prevented the development of PAH by maintaining mean pulmonary artery pressure within the normal range and attenuated right ventricular hypertrophy. With late treatment, tadalafil tended to increase the partial pressure of oxygen in arterial blood and dose-dependently improved the survival rate by 55%, 60%, and 70% at 0.5, 2.5, and 10 mg /kg per day, respectively, versus 40% in the MCTcontrol group. Both early and late treatments with tadalafil were associated with elevated lung cyclic guanosine monophosphate (cGMP). These results suggest that tadalafil relaxes pulmonary arteries by elevating cGMP in lungs and extend survival time by improving pulmonary hemodynamics even when treatment occurs in the late phase of PAH. Thus, it is expected that tadalafil may be an effective, once-daily treatment option in humans with PAH.

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Role of inhibition of nitric oxide production in monocrotaline-induced pulmonary hypertension

Cited by 36 publications

References 32 publications

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension

Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

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