Gene Therapy by Targeted Adenovirus-mediated Knockdown of Pulmonary Endothelial Tph1 Attenuates Hypoxia-induced Pulmonary Hypertension

Morecroft, Ian; White, Katie; Caruso, Paola; Nilsen, Margaret; Loughlin, Lynn; Alba, Raúl; Reynolds, Paul N.; Danilov, Sergei M.; Baker, Andrew H.; MacLean, Margaret R.

doi:10.1038/mt.2012.70

Cited by 48 publications

(42 citation statements)

References 51 publications

(91 reference statements)

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“…Tph expression and 5-HT synthesis have been shown to be increased in pulmonary endothelial cells from patients with IPAH and hypoxia-induced PAH in rats (16,19). The adenovirus-mediated knockdown of pulmonary endothelial Tph-1 has been shown to attenuate hypoxia-induced PH (28); in addition, Tph -/mice display markedly reduced plasma levels of 5-HT (29). These data indicate that Tph-1 plays an important role in the development of PAH.…”

Section: Discussionmentioning

confidence: 91%

4-Chloro-DL-phenylalanine protects against monocrotaline-induced pulmonary vascular remodeling and lung inflammation

Bai¹,

Wang²,

Liu³

et al. 2013

International Journal of Molecular Medicine

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The present study was performed to investigate the effects of 4-chloro-DL-phenylalanine (PCPA), a tryptophan hydroxylase (Tph) inhibitor (TphI), on pulmonary vascular remodeling and lung inflammation in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Animal models of PAH were established using Sprague-Dawley (SD) rats by a single intraperitoneal injection of MCT (60 mg/kg). PCPA (50 or 100 mg/kg/day) was administered to the rats with PAH. On day 22, hemodynamic measurements and morphological observations of the lung tissues were performed. The levels of Tph-1 and serotonin transporter (SERT) in the lungs were analyzed by immunohistochemistry and western blot analysis. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 and inflammatory cytokines were assayed by western blot analysis. The activity of MMP-2 and MMP-9 was evaluated by gelatin zymography (GZ). MCT markedly promoted PAH, increased the right ventricular hypertrophy index, pulmonary vascular remodeling, lung inflammation and mortality, which was associated with the increased expression of Tph-1, SERT, MMP-2/-9, TIMP-1/-2 and inflammatory cytokines. PCPA markedly attenuated MCT-induced pulmonary vascular remodeling and lung inflammation, inhibited the expression of Tph-1 and SERT and suppressed the expression of MMP-2/-9, TIMP-1/-2, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1). These findings suggest that the amelioration of MCT-induced pulmonary vascular remodeling and lung inflammation by PCPA is associated with the downregulation of Tph-1, SERT, MMP/TIMP and inflammatory cytokine expression in rats.

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Section: Discussionmentioning

confidence: 91%

4-Chloro-DL-phenylalanine protects against monocrotaline-induced pulmonary vascular remodeling and lung inflammation

Bai¹,

Wang²,

Liu³

et al. 2013

International Journal of Molecular Medicine

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“…Serotonin has been implicated in the PH observed in the SERT 1 mouse (38), hypoxic rodents (38)(39)(40), the sugen/hypoxic rodent (41), and dexfenfluramine-treated female mice (18). In these models, estrogen plays a causative role in the development of PH.…”

Section: Discussionmentioning

confidence: 99%

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Mair

Lü

et al. 2015

Am J Respir Crit Care Med

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Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH).Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs). Methods:We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs). We also determined the development of pulmonary hypertension in male and female mice deficient in Smad1.Measurements and Main Results: Platelet-derived growth factor, estrogen, and serotonin induced proliferation only in non-PAH female hPASMCs. Female non-PAH hPASMCs exhibited reduced messenger RNA and protein expression of BMPR-II, the signaling intermediary Smad1, and the downstream genes, inhibitors of DNA binding proteins, Id1 and Id3. Induction of phospho-Smad1/5/8 and Id protein by BMP4 was also reduced in female hPASMCs. BMP4 induced proliferation in female, but not male, hPASMCs. However, small interfering RNA silencing of Smad1 invoked proliferative responses to BMP4 in male hPASMCs. In male hPASMCs, estrogen decreased messenger RNA and protein expression of Id genes. The estrogen metabolite 4-hydroxyestradiol decreased phosphoSmad1/5/8 and Id expression in female hPASMCs while increasing these in males commensurate with a decreased proliferative effect in male hPASMCs. Female Smad1 1/2 mice developed pulmonary hypertension (reversed by ovariectomy). Conclusions:We conclude that estrogen-driven suppression of BMPR-II signaling in non-PAH hPASMCs derived from women contributes to a pro-proliferative phenotype in hPASMCs that may predispose women to PAH.

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“…Serotonin can also be synthesized in and released from PAECs in response to hypoxia. In line with this, conditioned media from PAECs exposed to hypoxia stimulates the proliferation of PASMCs via a serotonin-dependent mechanism [18]. In addition, PAECs from iPAH patients produce decreased amounts of nitric oxide and apelin, both of which suppress proliferation of PASMCs [19,20].…”

Section: Introductionmentioning

confidence: 83%

“…Serotonin is thought to play an important role in the pathogenesis of PAH as it promotes both PASMC proliferation and pulmonary artery constriction [10]. As discussed above, serotonin can be synthesized in and released from PAECs [17,18] mediating both proliferation and contraction of neighbouring PASMCs via actions at the serotonin transporter and serotonin receptors [10]. It was previously thought that paracrine signalling was responsible for the actions of serotonin in the pulmonary vasculature; however evidence suggests that Cx43 can mediate serotonin signalling between rat PAECs and rat PASMCs [33].…”

Section: Connexins and The Pulmonary Vasculaturementioning

confidence: 99%

Connexin-mediated regulation of the pulmonary vasculature

Dempsie

Martin

Upton

2015

Biochemical Society Transactions

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Pulmonary arterial hypertension (PAH) is a complex, multi-factorial disorder characterized by both constriction and remodelling of the distal pulmonary vasculature. This leads to increased pulmonary pressures and eventually right heart failure. Current drugs, which primarily target the vasoconstriction, serve only to prolong life and novel therapies targeting both the vasoconstriction and the remodelling are required. Aberrant signalling between cells of the pulmonary vasculature has been associated with the development of PAH. In particular, endothelial dysfunction can lead to hyperplasia of the underlying medial layer. Connexins are a family of transmembrane proteins which can form intercellular communication channels known as gap junctions. This review will discuss recent evidence which shows that connexins play a role in regulation of the pulmonary vasculature and that dysregulation of connexins may contribute to PAH pathogenesis. Interaction of connexins with signalling pathways relevant to the pathogenesis of PAH, such as bone morphogenetic protein (BMP), serotonin and oestrogen are discussed.

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Gene Therapy by Targeted Adenovirus-mediated Knockdown of Pulmonary Endothelial Tph1 Attenuates Hypoxia-induced Pulmonary Hypertension

Cited by 48 publications

References 51 publications

4-Chloro-DL-phenylalanine protects against monocrotaline-induced pulmonary vascular remodeling and lung inflammation

4-Chloro-DL-phenylalanine protects against monocrotaline-induced pulmonary vascular remodeling and lung inflammation

Sex Affects Bone Morphogenetic Protein Type II Receptor Signaling in Pulmonary Artery Smooth Muscle Cells

Connexin-mediated regulation of the pulmonary vasculature

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