Mediators and modulators of pulmonary arterial hypertension

Said, Sami I.

doi:10.1152/ajplung.00546.2005

Cited by 55 publications

(57 citation statements)

References 152 publications

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“…Changes in the pulmonary vasculature are found in the hypoxic NEP Ϫ/Ϫ mouse, which are similar to those found in large animal models of hypoxic PHTN that closely parallel human disease and are usually not associated with mouse models of chronic hypoxic PHTN. [1][2][3][4][5][6] We believe that further work with the NEP Ϫ/Ϫ mouse model of chronic hypoxic PHTN may lead to the identification of new therapeutic strategies or targets to limit or reverse this important clinical problem.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 These structural changes, together with derangements in vascular tone, are major contributors to the severity of chronic hypoxic PHTN. [1][2][3][4][5][6] However, mechanisms that regulate susceptibility to, and severity of, chronic hypoxic PHTN and vascular remodeling remain poorly understood. Currently available treatments for chronic hypoxic PHTN are also inadequate.…”

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confidence: 99%

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Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Dempsey

Wick

Karoor³

et al. 2009

The American Journal of Pathology

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Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder. Chronic hypoxic pulmonary hypertension (PHTN) is a major clinical problem, complicating most lung and heart disorders. 1,2 In large animal models of chronic hypoxic PHTN that closely resemble human disease, the earliest pulmonary artery (PA) smooth muscle cell (SMC) proliferative changes occur at the medial/adventitial border. 3 Growth and migration of SMC and myofibroblasts in distal vessels is also a prominent feature. 4,5 These structural changes, together with derangements in vascular tone, are major contributors to the severity of chronic hypoxic PHTN. [1][2][3][4][5][6] However, mechanisms that regulate susceptibility to, and severity of, chronic hypoxic PHTN and vascular remodeling remain poorly understood. Currently available treatments for chronic hypoxic PHTN are also inadequate.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Dempsey

Wick

Karoor³

et al. 2009

The American Journal of Pathology

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“…In response to CS, the hyper-expression of the PAR-2 in FVB mice resulted in a series of alterations in gene expression of vasoconstrictors, vasodilators and growth factors involved in the process of vascular remodelling [22][23][24][25][26]. The increased muscularisation of small vessels was preceded by enhanced production of growth factors involved in fibroblast-SMC transaction (PDGF and TGF-b) [27,28] and vascular cell proliferation (PDGF) [29,30], and by an imbalance between vasoconstrictors (especially ET-1) and vasodilators (i.e.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Cunto¹,

Cardini²,

Cirino³

et al. 2010

Eur Respir J

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The mechanism(s) involved in the development of pulmonary hypertension (PH) in COPD is still the object of investigation. Cigarette smoke (CS) may lead to remodelling of intrapulmonary vessels and dynamic changes in vascular function, at least in some smokers. A role for proteases in PH has been recently put forward.We investigated, in smoking mice, the role of protease-activated receptor (PAR)-2 in the pathogenesis of PH associated with emphysema.We demonstrated that CS exposure can modulate PAR-2 expression in mouse lung. Acute CS exposure induces in wildtype (WT) and in transgenic mice over-expressing PAR-2 (FVB PAR-2-TgN ) a similar degree of neutrophil influx in bronchoalveolar lavage fluids. After chronic CS exposure WT and FVB PAR-2-TgN mice show emphysema, but only transgenic mice develop muscularisation of small intrapulmonary vessels that precedes the development of PH (,45% increase) and right ventricular hypertrophy. Smoking in FVB PAR-2-TgN mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (i.e. vascular endothelial growth factor, endothelial nitric oxide synthase and inducible nitric oxide synthase) and enhanced production of growth factors involved both in fibroblast-smooth muscle cell transaction (i.e. platelet-derived growth factor (PDGF) and transforming growth factor b) and vascular cell proliferation (PDGF). PAR-2 signalling can influence the production and release of many factors, which may play a role in the development of PH in smokers.

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“…VIP exerts many of the actions highlighted by deletion of its gene, including: 1) increased generation of cyclic adenosine monophosphate (cAMP) and resultant protein kinase (PK)A activation; 2) enhancement of NOS3 activity and NO production via activation of BH4 [21], and hence of guanylate cyclase activity; 3) neutralisation of the contractile effect of endothelin on pulmonary arterial segments and abrogation of the heightened expression of lung endothelin receptors A and B during hypoxia [22]; 4) suppression of PASMC proliferation by In addition to its vascular effects, VIP has a number of important anti-inflammatory effects, including: 1) modulation of T-cell proliferation and activation; 2) inhibition of nuclear factor-kB activation; 3) suppression of pro-inflammatory cytokines TNF-a, IL-6, IL-12, IL-18, chemokine regulated on activation, normal T-cell expressed and secreted (RANTES), and inducible NOS; and 4) upregulation of anti-inflammatory IL-10 [24].…”

Section: Discussionmentioning

confidence: 99%

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

Hamidi

Prabhakar²,

Said³

2007

Eur Respir J

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The pathogenesis of idiopathic pulmonary arterial hypertension (PAH) remains poorly understood. The present authors recently reported that mice with vasoactive intestinal peptide (VIP) gene disruption show a spontaneous phenotype of PAH, with pulmonary vascular remodelling and lung inflammation.To explore the underlying molecular mechanisms in this model, it was examined whether absence of the VIP gene might alter the expression of additional genes involved in the pathogenesis of PAH, as single-gene deletions, in the absence of hypoxia, rarely result in significant pulmonary vascular remodelling.Lung tissue from mice with targeted disruption of the vasoactive intestinal peptide gene (VIP -/-mice) and from control mice was subjected to whole-genome gene microarray analysis, and the results validated with quantitative, real-time PCR. Lungs from VIP -/-mice showed a wide range of significant gene expression alterations, including overexpression of genes that promote pulmonary vascular smooth muscle cell proliferation, underexpression of antiproliferative genes and upregulation of pro-inflammatory genes.In conclusion, vasoactive intestinal peptide is a pivotal modulator of genes controlling the pulmonary vasculature, its deficiency alone resulting in gene expression alterations that can readily explain both the vascular remodelling and associated inflammatory response in pulmonary arterial hypertension. The present findings shed more light on the molecular mechanisms of pulmonary arterial hypertension, and could lead to better understanding of the pathogenesis of human pulmonary arterial hypertension, and hence to improved therapy. KEYWORDS: Gene expression and regulation, pulmonary hypertension, quantitative PCR, right heart failure T he present authors recently described a model of pulmonary hypertension in airbreathing, nonhypoxaemic mice with targeted disruption of the vasoactive intestinal peptide (VIP) gene (VIP -/-mice) [1]. The pulmonary vascular abnormalities in these mice, notably pulmonary vascular smooth muscle and collagen proliferation, and right ventricular (RV) hypertrophy are reminiscent of those seen in idiopathic pulmonary arterial hypertension (IPAH). There was also evidence of lung inflammation, which may contribute to the pathogenesis of IPAH. Both the vascular remodelling and inflammation were markedly attenuated by VIP replacement [1]. This mouse model, however, differs from the human disease in several respects: 1) pulmonary hypertension is of a moderate degree; 2) despite often pronounced medial thickening, intimal proliferation and plexiform lesions are not observed; and 3) in contrast to the clinical condition, the mouse phenotype is more prominently expressed in males than in females.The purpose of the present study was to uncover the molecular mechanisms by which disruption of the VIP gene could lead to expression of pulmonary arterial hypertension (PAH), pulmonary vascular remodelling, RV hypertrophy and lung inflammation. VIP has long been identified as a pulmonary, as well ...

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Mediators and modulators of pulmonary arterial hypertension

Abstract: Said, Sami I. Mediators and modulators of pulmonary arterial hypertension.

Cited by 55 publications

References 152 publications

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion: Table 1—

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