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Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased right ventricular systolic pressure (RVSP), vasoconstriction and inflammation. The heritable form of PAH (HPAH) is usually (>80%) caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene. Existing treatments for PAH typically focus on the end-stage sequelae of the disease, but do not address underlying mechanisms of vascular obstruction and blood flow and thus, in the long run, have limited effect because they treat the symptoms rather than the cause. Over the past decade, improved understanding of the molecular mechanisms behind the disease has enabled us to consider several novel therapeutic pathways. These include approaches directed toward BMPR2 gene expression, alternative splicing, downstream BMP signaling, metabolic pathways and the role of estrogens and estrogenic compounds in BMP signaling. It is likely that, ultimately, only one or two of these pathways will generate meaningful treatment options, however the potential benefits to PAH patients are still likely to be significant.

SUBMITTER: West J

PROVIDER: S-EPMC4396626 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension.

West James J Austin Eric E Fessel Joshua P JP Loyd James J Hamid Rizwan R

Drug discovery today 20140502 8

Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arterial remodeling, increased right ventricular systolic pressure (RVSP), vasoconstriction and inflammation. The heritable form of PAH (HPAH) is usually (>80%) caused by mutations in the bone morphogenic protein receptor 2 (BMPR2) gene. Existing treatments for PAH typically focus on the end-stage sequelae of the disease, but do not address underlying mechanisms of vascular obstruction and blood flow and thus, ...[more]

PMID: 24794464

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Project description:ObjectiveMutations in BMPR2 (bone morphogenetic protein receptor 2) are associated with familial and sporadic pulmonary arterial hypertension (PAH). The functional and molecular link between loss of BMPR2 in pulmonary artery smooth muscle cells (PASMC) and PAH pathogenesis warrants further investigation, as most investigations focus on BMPR2 in pulmonary artery endothelial cells. Our goal was to determine whether and how decreased BMPR2 is related to the abnormal phenotype of PASMC in PAH.MethodsSMC-specific Bmpr2-/- mice (BKOSMC) were created and compared to controls in room air, after 3 weeks of hypoxia as a second hit, and following 4 weeks of normoxic recovery. Echocardiography, right ventricular systolic pressure, and right ventricular hypertrophy were assessed as indices of pulmonary hypertension. Proliferation, contractility, gene and protein expression of PASMC from BKOSMC mice, human PASMC with BMPR2 reduced by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation were compared to controls, to investigate the phenotype and underlying mechanism.ResultsBKOSMC mice showed reduced hypoxia-induced vasoconstriction and persistent pulmonary hypertension following recovery from hypoxia, associated with sustained muscularization of distal pulmonary arteries. PASMC from mutant compared to control mice displayed reduced contractility at baseline and in response to angiotensin II, increased proliferation and apoptosis resistance. Human PASMC with reduced BMPR2 by small interference RNA, and PASMC from PAH patients with a BMPR2 mutation showed a similar phenotype related to upregulation of pERK1/2 (phosphorylated extracellular signal related kinase 1/2)-pP38-pSMAD2/3 mediating elevation in ARRB2 (β-arrestin2), pAKT (phosphorylated protein kinase B) inactivation of GSK3-beta, CTNNB1 (β-catenin) nuclear translocation and reduction in RHOA (Ras homolog family member A) and RAC1 (Ras-related C3 botulinum toxin substrate 1). Decreasing ARRB2 in PASMC with reduced BMPR2 restored normal signaling, reversed impaired contractility and attenuated heightened proliferation and in mice with inducible loss of BMPR2 in SMC, decreasing ARRB2 prevented persistent pulmonary hypertension.ConclusionsAgents that neutralize the elevated ARRB2 resulting from loss of BMPR2 in PASMC could prevent or reverse the aberrant hypocontractile and hyperproliferative phenotype of these cells in PAH.

Dataset Information

Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension.

Publications

Rescuing the BMPR2 signaling axis in pulmonary arterial hypertension.

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