Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension

Orte, Carlos; Polak, Julia M.; Haworth, Sheila G.; Yacoub, Magdi H.; Morrell, Nicholas W.

doi:10.1002/1096-9896(2000)9999:9999<::aid-path715>3.0.co;2-q

Cited by 112 publications

(75 citation statements)

References 20 publications

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“…3,18,20 The evidence, supported by our findings, suggests that the intimal lesion is composed of myofibroblast-like cells, which stain positively for ␣-smooth muscle actin and vimentin, and that the expression of endothelium-specific markers is confined to cells lining the vascular lumen. 3,21 The plexiform lesion would appear to consist of a proliferation of endothelial cells supported by a myofibroblast stroma. 3,4,22,23 In summary, the present study identifies predominantly endothelial cells but also myofibroblast cells comprising intimal lesions as the sites of pulmonary vascular expression of BMPR-II in PPH and secondary PH.…”

Section: Discussionsupporting

confidence: 58%

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

et al. 2002

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Background-Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-␤ (TGF-␤) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). Methods and Results-Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-␤ by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (nϭ11, including 3 familial cases) or secondary pulmonary hypertension (nϭ6) and from unused donor lungs (nϭ4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-␤RII or the endothelial marker CD31. Conclusions-The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension.

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Section: Discussionsupporting

confidence: 58%

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

et al. 2002

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“…A polymorphism in the angiotensinconverting enzyme gene is known to be associated with the manifestation of pulmonary hypertension. 19 Increased angiotensin-converting enzyme expression is observed in plexiform lesions in PAH, 20 and angiotensin-converting enzyme inhibition seems to delay pulmonary vascular neointimal formation. 21 Therefore, the renin-angiotensinaldosterone system (RAAS) represents a group of candidate genes that could modify disease severity and/or age at diagnosis of individuals predisposed to develop PAH.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

et al. 2010

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Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1-and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1-and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11bHSD2 (11b-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.

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“…However, the existence of differences in pulmonary endothelial function between the PAH etiologic types remains a possibility, and we therefore hypothesized that PCEB-ACE activity might differ between common PAH types. Furthermore, preserved pulmonary capillary endothelial ACE immunoreactivity and expression have previously been described in patients with IPAH, but the functional significance of this finding was unknown (13,14). Our data provide evidence that these preserved ACE levels are metabolically active.…”

Section: Pulmonary Arterial Hypertension (Pah) Remainsmentioning

confidence: 78%

“…Our data thus imply that PCEB-ACE activity (as expressed using the enzyme activity parameters in the equation described in Patients and Methods) is preserved. These findings provide the first functional confirmation that the previously described preserved pulmonary capillary ACE expression in IPAH is enzymatically active (13,14).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension

Langleben¹,

Orfanos²,

Giovinazzo³

et al. 2008

Arthritis & Rheumatism

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Objective. Pulmonary endothelial dysfunction is intertwined with the development and progression of pulmonary arterial hypertension (PAH). Pulmonary endothelium is an active metabolic tissue in healthy human subjects. This study was undertaken to determine the effects of PAH on pulmonary endothelial angiotensin-converting enzyme (ACE) activity and to identify differences between common PAH types, i.e., PAH related to connective tissue disease (PAH-CTD) versus idiopathic PAH (IPAH).Methods. Nineteen patients with PAH-CTD, 25 patients with IPAH, and 23 control subjects were evaluated. The single-pass transpulmonary percent metabolism (%M) and hydrolysis (both reflecting enzyme activity per capillary) of an ACE synthetic substrate were determined. In addition, the calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), was determined.Results. The %M values in patients with PAH-CTD (mean ؎ SEM 53.6 ؎ 3.6%) were significantly reduced compared with those in control subjects (P < 0.01) and those in patients with IPAH (P < 0.03), but were similar between the IPAH and control groups (mean ؎ SEM 66.2 ؎ 3.6% and 74.7 ؎ 2.7%, respectively). Substrate hydrolysis was also significantly reduced in patients with PAH-CTD. The FCSA/BSA was significantly reduced in patients with PAH-CTD (mean ؎ SEM 1,068 ؎ 118 ml/minute/m 2 ) and in patients with IPAH (1,443 ؎ 186 ml/minute/m 2 ) compared with that in controls (2,948 ؎ 245 ml/minute/m 2 ; P < 0.01 for both). At a given cardiac index, the FCSA/BSA tended to be lower in the PAH-CTD group than in the IPAH group. Moreover, unlike in IPAH, a linear relationship between the FCSA/BSA and the diffusing capacity for carbon monoxide (DLCO) was observed in PAH-CTD (r ‫؍‬ 0.54, P < 0.03).Conclusion. The metabolically functional pulmonary capillary bed appears to be reduced to an equal extent in PAH-CTD and IPAH. However, %M and hydrolysis appear to be reduced in PAH-CTD but not in IPAH, reflecting relatively diminished ACE activity on the pulmonary capillary endothelial cells of patients with PAH-CTD, and showing that pulmonary endothelial metabolic function differs between PAH types. This study also provides the first functional evidence that a

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Expression of pulmonary vascular angiotensin-converting enzyme in primary and secondary plexiform pulmonary hypertension

Cited by 112 publications

References 20 publications

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Pulmonary capillary endothelial metabolic dysfunction: Severity in pulmonary arterial hypertension related to connective tissue disease versus idiopathic pulmonary arterial hypertension

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