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.

T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

“…80%) caused by mutations in the BMPR2 . 7 In animal models, it has been shown that greater endothelial injury and enhanced infl ammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension. 8 Diff erent studies have shown increased levels of cytokines in PAH, including the proinfl ammatory cytokines IL-1 b , IL-2, IL-4, IL-6, IL-8, IL-12p70, tumor necrosis factor (TNF)-a , monocyte chemoattractant protein-1, 9,10 and the cytokine-like hormone leptin.…”

Bone Morphogenetic Protein Signaling in Pulmonary Arterial Hypertension

“…Histological evidence suggests markedly downregulated BMPR2 expression in the pulmonary vasculature of patients with mutations and moderately decreased BMPR2 expression in that of IPAH patients even without known mutations [8], suggesting deficiency of BMPR2 signaling may be a wider phenomenon beyond HPAH. Premature terminations result in the activation of the nonsense-mediated decay pathway and cause disease due to functional haploinsufficiency [143,212]. On the other hand, amino acid substitutions may lead to loss of kinase activity and aberrant trafficking of misfolded BMPR2 in the endoplasmic reticulum and cause disease by dominantnegative effects [60,212].…”

“…Premature terminations result in the activation of the nonsense-mediated decay pathway and cause disease due to functional haploinsufficiency [143,212]. On the other hand, amino acid substitutions may lead to loss of kinase activity and aberrant trafficking of misfolded BMPR2 in the endoplasmic reticulum and cause disease by dominantnegative effects [60,212]. Some BMPR2 mutants may reach the cell membrane but form clusters or otherwise exhibit altered associations with membrane domains, including caveolae, lipid rafts, or clathrin-coated pits [94].…”

“…These approaches aim to rescue BMPR2 expression directly or enhance BMP signaling by targeting other components of the pathway [212]. Interestingly, current vasodilatory PAH drugs such as sildenafil [221] and prostacyclin analogues [220] partly rescue SMAD/Id signaling via cyclic adenosine monophosphate and cyclic guanosine monophosphate, supporting the therapeutic benefits of enhancing BMP signaling.…”

Progress in the diagnosis and management of pulmonary hypertension in children

“…Mutations in this gene have been involved in multiple signaling pathways implicated in the development of PH. Our current understanding of BMPR2 regulation suggests that although 80% of familial PH is caused by a BMPR2 mutation, almost all forms of PH share abnormal BMPR2 signaling [44**]. …”