Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension.

  title={Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension.},
  author={Ann Marie Reynolds and Wei Xia and Mark D. Holmes and Sandra Hodge and Sergei M. Danilov and David T. Curiel and Nicholas W. Morrell and Paul N Reynolds},
  journal={American journal of physiology. Lung cellular and molecular physiology},
  volume={292 5},
Idiopathic pulmonary arterial hypertension (PAH) is characterized by proliferation of pulmonary vascular endothelial and smooth muscle cells causing increased vascular resistance and right heart failure. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are believed to cause the familial form of the disease. Reduced expression of BMPR2 is also noted in secondary PAH. Recent advances in the therapy of PAH have improved quality of life and survival, but many patients continue to… 

Targeted gene delivery of BMPR2 attenuates pulmonary hypertension

Results indicate therapeutic potential for upregulation of the BMPR2 axis in PAH, which may be, in part, mediated by countering the remodelling effects of TGF-b.

Targeted gene delivery of BMPR2 attenuates pulmonary hypertension

Therapeutic potential for upregulation of the BMPR2 axis in PAH is indicated, in part, mediated by countering the remodelling effects of TGF-&bgr;.

Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type II receptor.

The ways in which manipulation of BMPR-II signaling might be targeted with the aim of preventing or reversing vascular remodeling and improving survival in patients with PAH are discussed.

The Role of Bone Morphogenetic Protein Receptor Type 2 (BMPR2) and the Prospects of Utilizing Induced Pluripotent Stem Cells (iPSCs) in Pulmonary Arterial Hypertension Disease Modeling

Currently available approaches in iPSC-based PAH disease modeling are summarized and how this technology could be harnessed for drug discovery and to widen the understanding of the pathophysiology of PAH is explored.

Targeting bone morphogenic protein receptor 2 (BMPR2) signalling to treat pulmonary arterial hypertension

  • L. Rubin
  • Medicine, Biology
    European Respiratory Journal
  • 2017
It is reported that BMPR2 mRNA expression is attenuated in PAH and that FK506 (tacrolimus), a BMPR 2 activator, produced no meaningful effects in a small, single-centre 16-week clinical trial in subjects with PAH due to a variety of aetiologies.

Expression of Mutant Bone Morphogenetic Protein Receptor II Worsens Pulmonary Hypertension Secondary to Pulmonary Fibrosis

The data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium, which could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis.

Pulmonary arterial hypertension: role of miRNAs in animal models and pathological samples

The aim of this project was to investigate the role of miRNAs in the development of PAH and to report the significant up-regulation of these miRNAAs in WT mice exposed to chronic hypoxia, and to demonstrate time and insult-dependent changes in a specific group if mi RNAs and this dysregulation was also confirmed in vitro in rat and human PA cells exposed in vitro.

Elafin Reverses Pulmonary Hypertension via Caveolin-1-Dependent Bone Morphogenetic Protein Signaling.

Elafin reverses obliterative changes in pulmonary arteries via elastase inhibition and caveolin-1-dependent amplification of BMPR2 signaling and promotes angiogenesis by increasing pSMAD-dependent and -independent BM PR2 signaling.

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

This work has shed light on promising new strategies by which dysregulated BMP/TGF-β might be modulated for therapeutic benefit in PAH and related conditions.



Bone Morphogenetic Protein 4 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension

Findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP 4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.

Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension.

Despite robust h BMPR2 expression in all lung lobes and within resistance PAs of treated rats, hBMPR2 did not lower mean PA pressure, pulmonary vascular resistance index, right ventricular hypertrophy, or remodeling of Resistance PAs, and this model of PAH did not ameliorate PAH.

Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension.

Results suggest abrogation of BMP signaling may be a common molecular pathogenesis in the development of PH with various pathophysiological events, including primary and hypoxic PH.

BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia.

The results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing.

Bone Morphogenetic Protein Receptor-2 Signaling Promotes Pulmonary Arterial Endothelial Cell Survival: Implications for Loss-of-Function Mutations in the Pathogenesis of Pulmonary Hypertension

The hypothesis that loss-of-function mutations in BMPR2 could lead to increased pulmonary EC apoptosis is supported, representing a possible initiating mechanism in the pathogenesis of pulmonary arterial hypertension.

Dysfunctional Smad Signaling Contributes to Abnormal Smooth Muscle Cell Proliferation in Familial Pulmonary Arterial Hypertension

Mutations in the bone morphogenetic protein type II receptor gene (BMPR2) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation

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

The cellular localization of BM PR-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.

Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle

Studies with SM22-tet-BMPRIIdelx4+ mice support the hypothesis that loss of BMPRII signaling in smooth muscle is sufficient to produce the pulmonary hypertensive phenotype and study the role of BMP signaling in postnatal vascular disease.

Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension.

It is concluded that mutations in BMPR-II heterogeneously inhibit BMP/Smad-mediated signalling by diverse molecular mechanisms, however, all mutants studied demonstrate a gain of function involving upregulation of p38(MAPK)-dependent proproliferative pathways.

Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-&bgr;1 and Bone Morphogenetic Proteins

It is concluded that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-&bgr;1 and BMPs and that altered integration of TGF; superfamily growth signals may contribute to the pathogenesis of PPH.