p38 Mitogen-Activated Protein Kinase Mediates the Sustained Phase of Hypoxic Pulmonary Vasoconstriction and Plays a Role in Phase I Vasodilation

Morrell, Eric D.; Tsai, Ben M.; Wang, Meijing; Crisostomo, Paul R.; Meldrum, Daniel R.

doi:10.1016/j.jss.2006.01.028

Cited by 14 publications

(8 citation statements)

References 48 publications

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“…IL-4 is also known to initiate activation of MEK subfamilies, including p42/p44 MEK/ERK, in bronchial smooth muscle and epithelial cells (52,60). It has been well documented that hypoxia up-regulates MEK subfamilies and acts as a proliferative stimulus in the pulmonary artery (53,61). In the present study, we showed that ERK, which is also a downstream signaling molecule of the VEGF pathway, is involved, at least in part, in this process.…”

Section: Discussionsupporting

confidence: 64%

IL-4 Is Proangiogenic in the Lung under Hypoxic Conditions

Yamaji-Kegan

Angelini

et al. 2009

The Journal of Immunology

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IL-4-mediated proangiogenic and proinflammatory vascular responses have been implicated in the pathogenesis of chronic lung diseases such as asthma. Although it is well known that hypoxia induces pulmonary angiogenesis and vascular alterations, the underlying mechanism of IL-4 on the pulmonary vasculature under hypoxic conditions remains unknown. In this context, we designed the present study to determine the functional importance of IL-4 for pulmonary angiogenesis under hypoxic conditions using IL-4 knockout (KO) animals. Our results show that hypoxia significantly increased IL-4Rα expression in wild-type (WT) control lungs. Even though hypoxia significantly up-regulated vascular endothelial growth factor (VEGF) receptor expression in the lungs of both genotypes, hypoxia-induced VEGF, VCAM-1, HIF-1α, and ERK phosphorylation were significantly diminished in IL-4 KO lungs as compared with WT control lungs. In addition, hypoxia-induced pulmonary angiogenesis and proliferating activities in the airway and pulmonary artery were significantly suppressed in IL-4 KO lungs as compared with WT control lungs. We also isolated primary lung fibroblasts from these genotypes and stimulated these cells with hypoxia. Hypoxia-induced VEGF production was significantly suppressed in lung fibroblasts from IL-4 KO mice. These in vitro results are in accordance with the in vivo data. Furthermore, we observed a significant increase of hypoxia-induced pulmonary angiogenesis in STAT6 KO mice similar to that in WT controls. In conclusion, IL-4 has proangiogenic properties in the lung under hypoxic conditions via the VEGF pathway, and this is independent of the STAT6 pathway.

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Section: Discussionsupporting

confidence: 64%

IL-4 Is Proangiogenic in the Lung under Hypoxic Conditions

Yamaji-Kegan

Angelini

et al. 2009

The Journal of Immunology

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“…The suggestion that VEGFR-2-independent pathways cause severe PH (54) led us to explore other activities contributing to the attenuated PH phenotype. Previous reports have demonstrated increased SMC proliferation to hypoxia both in vivo and in vitro via the protein kinase C (PKC)/MAPK pathway (24,31,60,61). In this study, compared with the hypoxia-alone group the combined hypoxia/ SU-5416 group had higher levels of phosphorylated MEK1/2 and ERK.…”

Section: Discussionmentioning

confidence: 46%

Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

Moreno‐Vinasco

Gomberg‐Maitland

Maitland

et al. 2008

Physiological Genomics

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Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33: 278 -291, 2008. First published February 26, 2008 doi:10.1152/physiolgenomics.00169.2007.-Pulmonary hypertension (PH) and cancer pathology share growth factor-and MAPK stressmediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1-3, PDGF receptor (PDGFR)-␤, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxiaexposed control animals, four groups were maintained at 10% inspired O 2 fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/ sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]-and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change Ͼ1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target. microarrays; SU-5416; bioinformatics PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) with a mean pressure of Ͼ25 mmHg at rest or 30 mmHg during exercise (43), with severe PH exhibiting PAP values Ͼ50 mmHg (2, 59). Severe PH manifests as both an acute and a chronic presentation, with chronic PH leading to progressive right ventricular (RV) systolic pressure overload and ventricular dilatation, resulting in gradual RV dysfunction, heart failure, and death (21). Idiopathic PH has an estimated annual incidence of 1-2 per million (1) with mutations of the bone morphogenetic protein receptor type 2 gene (BMPR2) identified in ϳ50% of cases of familial PH (7). However, because only 20% of persons with a BMPR2 mutation develop PH (32), external stimuli, coupled with a susceptible genetic profile,...

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“…Pulmonary artery vasoreactivity is influenced by the integrity of the endothelial cell layer and the inflammatory state of the vasculature [32][33][34]. Acute hypoxic pulmonary vasoconstriction is associated with smooth muscle cell contraction, inflammation, and cytokine release [32,[35][36][37][38][39]. Estrogen has been shown to decrease inflammation and to stabilize cellular integrity [2,18].…”

Section: Discussionmentioning

confidence: 99%