Nogo
was first identified as an inhibitor of neuronal axonal regeneration. Recently,
Nogo-B
was implicated in the proliferative and anti-apoptotic remodeling in systemic arteries; reduced
Nogo-B
expression was seen in remodeled mouse femoral arteries following injury. Pulmonary arterial hypertension (PAH) is also characterized by proliferative/anti-apoptotic remodeling in pulmonary arteries (PA), sparing systemic vessels. PAH PA smooth muscle cells (PASMC) are characterized by mitochondrial hyperpolarization (increased ΔΨm), decreased production of reactive oxygen species (ROS) (suppressing mitochondria-dependent apoptosis), down-regulation of Kv1.5 and activation of the transcription factor NFAT (promoting contraction and proliferation). We found that in contrast to systemic vessels,
Nogo-B
expression is significantly increased in vivo and in vitro in PAs and PASMCs from patients (n=6) and mice (n=42) with PAH, compared to normals. We hypothesized that
Nogo
is involved in the pathogenesis of PAH
. Nogo
−/−
mice (n=7) had a normal phenotype and, in contrast to
Nogo
+/+
, did not develop chronic hypoxia (CH)-induced PAH assessed invasively (catheterization, RV/LV+Septum) and non-invasively (pulmonary artery acceleration time and treadmill performance) (n=7, Table
). CH-
Nogo
+/+
PASMC had the expected increase in ΔΨm (measured by TMRM), decreased ROS (MitoSOX), increased [Ca
++
]
i
(FLUO3), decreased Kv1.5 (immunohistochemistry) and NFAT activation (nuclear translocation). None of these changes occurred in CH-
Nogo
−/−
PASMC while all were induced in normoxic
Nogo
+/+
PASMC by adenoviral over-expression of
Nogo-B
. Heterozygote CH-
Nogo
+/−
(n=7) values were between
Nogo
−/−
and
Nogo
+/+
suggesting a gene dose-dependent effect.
Nogo
is over-expressed in human and rodent PAH and induces critical features of the PAH phenotype.
Nogo
targeting might represent a novel and selective therapeutic strategy for PAH.
Table
Six Cases of Hemoptysis with Angiogenesis from Non-Bronchial Systemic Arteries
