Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

Zhao, Lan; Al-Tubuly, Rida; Sebkhi, Abdelkrim; Owji, Ali Akbar; Nunez, Derek J.; Wilkins, Martin R.

doi:10.1111/j.1476-5381.1996.tb16025.x

Cited by 49 publications

(35 citation statements)

References 31 publications

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“…As well known, the increase in vasoconstricting and proproliferative factors and the decrease in vasodilating and antiproliferative mediators contribute to HPVSR (Kourembanas et al, 1997;Steudel et al, 1998;Elton et al, 1992;Zhao et al, 1996;Du et al, 1997). Human U-II is a cyclic neuropeptide initially isolated from fish spinal cords (Zhang et al, 2002), which has recently been cloned from humans.…”

Section: Discussionmentioning

confidence: 93%

Effects of hydrogen sulfide on hypoxic pulmonary vascular structural remodeling

et al. 2006

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Section: Discussionmentioning

confidence: 93%

Effects of hydrogen sulfide on hypoxic pulmonary vascular structural remodeling

et al. 2006

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“…By stimulation experiments, we found that miR-204 expression is down-regulated by PDGF, endothelin-1, and angiotensin II, which are all well known to be involved in the pathogenesis of pulmonary hypertension (Zhao et al, 1996;Archer and Rich, 2000). Because PDGF, endothelin-1, and angiotensin II signaling is mainly mediated by STAT3 (Yellaturu and Rao, 2003;Banes-Berceli et al, 2007), the effect of STAT3 inhibition by small interfering RNA (siRNA) on miR-204 was also investigated.…”

Section: Mir-204 Is Aberrantly Expressed In Human Pah-pasmcsmentioning

confidence: 94%

Role for miR-204 in human pulmonary arterial hypertension

Courboulin¹,

Paulin²,

Giguère³

et al. 2011

J Cell Biol

148

219

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Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease. role of miR-204 in the etiology of PAH. Interestingly, using in silico and microarray gene expression analyses, we observed that among the 461 predicted targets of miR-204 (TargetScan 5.1), only 165 were increased by artificial miR-204 inhibition in control human PASMCs (n = 2 patients; Fig. S1 C). In accordance with the pro-proliferative and antiapoptotic phenotypes seen in PAH, several Src-STAT3-and NFAT-related genes were identified (Fig. S1 C). miR-204 expression is decreased in human PAH and correlates with PAH severityTo investigate the expression pattern of miR-204 in normal and pulmonary hypertensive lungs, we examined miR-204 expression levels in (a) lung biopsies from 8 individuals with nonfamilial PAH compared with biopsies from 8 individuals without pulmonary hypertension, (b) lungs from 6 mice with hypoxia-induced pulmonary hypertension compared with 5 control littermates, and (c) lungs from 5 rats with monocrotaline (MCT)-induced pulmonary hypertension compared with 10 control littermates ( Fig. 1 A). We found decreased levels of miR-204 in human and rodent pulmonary hypertensive lung tissues compared with normotensive lung samples. To characterize whether down-regulated miR-204 levels were specific to the lung in rats with pulmonary hypertension, we compared organ-specific levels of miR-204 between normal and pulmonary hypertensive rats (Fig. 1 B). Even if we were able to detect minimal amounts of miR-204 in most organs, miR-204 levels were only down-regulated in the lung and PAs but not in the aorta, liver, heart, and kidney in rats 3 wk after MCT injection (pulmonary hypertensive rats) compared with non-pulmonary hypertensive rats (Fig. 1 B).To test whether miR-204 down-regulation correlated with disease progression, we studied humans, mice, a...

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“…Chronic hypoxia regulates the expression of RAS in a number of tissues, including the kidney (Neylon et al 1996), the lung (Zhao et al 1996), the heart (Morrell et al 1997) and the pancreas (Chan et al 2000). In the carotid body, Ang II-binding sites have been demonstrated by in vitro autoradiography (Allen 1998).…”

Section: Discussionmentioning

confidence: 99%

Chronic hypoxia upregulates the expression and function of AT(1) receptor in rat carotid body

Leung¹,

Sy²,

Fung³

2000

Journal of Endocrinology

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In the present study, the effects of chronic hypoxia on the expression and localization of angiotensin II (Ang II) receptors are investigated by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and by immunohistochemistry. The effect of chronic hypoxia on the carotid body chemoreceptor activity was also examined by in vitro electrophysiology. Results from RT-PCR revealed that chronic hypoxia exhibited differential effects on the gene expression of Ang II receptors, namely AT 1 and AT 2 , in the carotid body. The mRNA expression for subtypes of the AT 1 receptor, AT 1a and AT 1b , was significantly increased in the carotid body with chronic hypoxia. To further investigate the localization of the AT 1 receptor, an immunohistochemical study was performed. The results showed that AT 1 receptor immunoreactivity was found in lobules of glomus cells in the carotid body and the immunoreactivity was more intense in chronic hypoxia than in normoxic controls. In vitro electrophysiological studies consistently demonstrated that chronic hypoxia enhanced the AT 1 receptor-mediated excitation of carotid body chemoreceptor activity. These data suggest that chronic hypoxia upregulates the transcriptional and post-transcriptional expression of AT 1 receptors in the rat carotid body. The upregulation of the expression also enhances AT 1 receptor-mediated excitation of the carotid body afferent activity. This might be important in the modulation of cardiorespiratory functions as well as fluid and electrolyte homeostasis during chronic hypoxia.

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Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

Cited by 49 publications

References 31 publications

Effects of hydrogen sulfide on hypoxic pulmonary vascular structural remodeling

Effects of hydrogen sulfide on hypoxic pulmonary vascular structural remodeling

Role for miR-204 in human pulmonary arterial hypertension

Chronic hypoxia upregulates the expression and function of AT(1) receptor in rat carotid body

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