Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lung

Wiener, Renda Soylemez; Cao, Yu; Hinds, Anne; Ramirez, María I.; Williams, Mary C.

doi:10.1002/jcb.21248

Cited by 83 publications

(82 citation statements)

References 45 publications

(85 reference statements)

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“…In the mouse lung, ACE-2 has been shown to be developmentally regulated, with mRNA highest at embryonic day 18.5, and to be expressed primarily in bronchiolar and alveolar epithelial cells [27]. In the human lung, airway epithelial cells are one of the first sites of contact by the SARS coronavirus during lung infection; moreover, ACE-2 has been shown to be the site to which the SARS virus binds to initiate tissue infection [28].…”

Section: Discussionmentioning

confidence: 99%

Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Uhal

Dang

et al. 2012

Eur Respir J

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Alveolar epithelial type II cells, a major source of angiotensin-converting enzyme (ACE)-2 in the adult lung, are normally quiescent but actively proliferate in lung fibrosis and downregulate this protective enzyme. It was, therefore, hypothesised that ACE-2 expression might be related to cell cycle progression.To test this hypothesis, ACE-2 mRNA levels, protein levels and enzymatic activity were examined in fibrotic human lungs and in the alveolar epithelial cell lines A549 and MLE-12 studied at postconfluent (quiescent) versus subconfluent (proliferating) densities.ACE-2 mRNA, immunoreactive protein and enzymatic activity were all high in quiescent cells, but were severely downregulated or absent in actively proliferating cells. Upregulation of the enzyme in cells that were progressing to quiescence was completely inhibited by the transcription blocker actinomycin D or by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). In lung biopsy specimens obtained from patients with idiopathic pulmonary fibrosis, immunoreactive enzyme was absent in alveolar epithelia that were positive for proliferation markers, but was robustly expressed in alveolar epithelia devoid of proliferation markers.These data explain the loss of ACE-2 in lung fibrosis and demonstrate cell cycle-dependent regulation of this protective enzyme by a JNK-mediated transcriptional mechanism. @ERSpublications Cell cycle-dependent regulation of ACE-2 by a JNK-mediated transcriptional mechanism explains ACE-2 downregulation in IPF

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Section: Discussionmentioning

confidence: 99%

Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Uhal

Dang

et al. 2012

Eur Respir J

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“…8A) supports the theory that ACE-2 limits the accumulation of ANG II produced by AECs in response to bleomycin. Recent studies by Weiner et al (24) showed that AECs are the main source of lung tissue ACE-2 in the mouse. Whether or not the decrease in ACE-2 mRNA induced by bleomycin is mediated by autocrine production of ANG II (14) will be an interesting and compelling question for further study.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis

Molina-Molina

Abdul-Hafez

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

171

194

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Earlier work from this laboratory showed that local generation of angiotensin (ANG) II is required for the pathogenesis of experimental pulmonary fibrosis and that ANG peptides are expressed robustly in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Angiotensin converting enzyme-2 (ACE-2) degrades the octapeptide ANG II to form the heptapeptide ANG1-7 and thereby limits ANG II accumulation. On this basis, we hypothesized that ACE-2 would be protective against experimental lung fibrogenesis and might be downregulated in human and experimental lung fibrosis. In lung biopsy specimens from patients with IPF, ACE-2 mRNA and enzyme activity were decreased by 92% ( P < 0.01) and 74% ( P < 0.05), respectively. ACE-2 mRNA and activity were also decreased similarly in the lungs of bleomycin-treated rats and C57-BL6 mice. In mice exposed to low doses of bleomycin, lung collagen accumulation was enhanced by intratracheal administration of either ACE-2-specific small interfering RNAs (siRNAs) or the peptide DX600, a competitive inhibitor of ACE-2 ( P < 0.05). Administration of either ACE-2 siRNA or DX600 significantly increased the ANG II content of mouse lung tissue above the level induced by bleomycin alone. Coadministration of the ANG II receptor antagonist saralasin blocked the DX600-induced increase in lung collagen. Moreover, purified recombinant human ACE-2, delivered to mice systemically by osmotic minipump, attenuated bleomycin-induced lung collagen accumulation. Together, these data show that ACE-2 mRNA and activity are severely downregulated in both human and experimental lung fibrosis and suggest that ACE-2 protects against lung fibrogenesis by limiting the local accumulation of the profibrotic peptide ANG II.

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“…This observation forms the basis of our proposal: namely, that activation of endogenous ACE2 can affect the balance between the two axes and prevent vascular remodeling and pathological events that lead to PH. Additional evidence confirms that ACE2 is central to pulmonary endothelial function and lung pathophysiology: (1) ACE2 is abundantly expressed in the pulmonary endothelium (8)(9)(10)(11); (2) ACE2 is significantly decreased in lung biopsies of patients with idiopathic pulmonary fibrosis (9); (3) bleomycin-induced pulmonary fibrosis and PH are associated with a decrease in ACE2 activity (9); (4) patients with PH have an increase in circulating endothelial cells (CEC) (12) due to high pressure in the pulmonary circuits and increased shear stress in the pulmonary vasculature (13), and ACE levels in the CEC of PH are significantly higher (unpublished observation); (5) ACE2 knockout mice exhibited severe acute respiratory distress syndrome, which is attenuated with administration of recombinant ACE2 (14); (6) Ang II up-regulates ACE and down-regulates ACE2 in patients with hypertension (15); and (7) Higher ACE2 activity with increased angiotensin-(1-7) formation has been reported in heart ventricles of patients with primary PH (16), suggesting a cardiopulmonary protective role for ACE2 (17). Collectively, these observations led us to propose that activation of endogenous ACE2 could have a protective effect against PH.…”

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confidence: 83%

Evidence for Angiotensin-converting Enzyme 2 as a Therapeutic Target for the Prevention of Pulmonary Hypertension

Ferreira

Shenoy²,

Yamazato³

et al. 2009

Am J Respir Crit Care Med

239

216

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Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.Keywords: renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease.Pulmonary hypertension (PH) presents a diverse etiology and is defined by a mean pulmonary arterial pressure of greater than 25 mm Hg at rest, or greater than 30 mm Hg with exercise (1). The most common causes of PH include chronic obstructive pulmonary disease (often caused by smoking), left heart failure, substance abuse, schistosomiasis, high altitude exposure, drugs, toxins (e.g., chemical warfare), and HIV infection (2, 3). It has been proposed that these risk factors, coupled with predisposing genetic factors, lead to an imbalance between vasoconstrictor and vasodilator mechanisms. This imbalance initiates a cascade of pathophysiological events in the lungs leading to PH (4). These events are suggested to be set in motion by pulmonary vascular endothelial dysfunction causing enhanced proliferation and activation of lung fibroblasts, leading to extracellular matrix formation and fibrosis, infiltration of inflammatory cells, increased production of proinflammatory cytokines, exaggerated pulmonary vascular remodeling, and smooth muscle hypertrophy (5, 6). Vasodilatory ther...

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Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lung

Cited by 83 publications

References 45 publications

Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis

Evidence for Angiotensin-converting Enzyme 2 as a Therapeutic Target for the Prevention of Pulmonary Hypertension

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