Biology Reference
In-Depth Information
monocytes/macrophages, T- and B-lymphocytes, and dendritic cells (Barnes and
Liu
1995
; Humbert et al.
2004
; Morrell et al.
2009
; Tuder et al.
2009
). Although
each cell type contributes to PAH, increased vasoconstriction is currently the main
target for investigative and approved therapies. Studies of PAH often involve use of
animal models, most commonly, the chronically hypoxic rat/mouse and monocrota-
line-treated rat (Stenmark et al.
2009
). Genetically manipulated mice are used to
study the role of specific genes in the pathogenesis of PAH: mice overexpressing
the serotonin transporter develop elevated mPAP and are more susceptible to
hypoxia-induced PAH (Dempsie et al.
2008
). Although such models
have provided insight into mediators of the disease and aided in the development
of drugs for PAH, species-specific function of certain targets, which will be
discussed below in relation to PDE1, may have resulted in their importance being
overlooked.
2 Role of Cyclic Nucleotides in PAH
Both adenosine 3
0
,5
0
-cyclic monophosphate (cAMP) and guanosine 3
0
,5
0
-cyclic
monophosphate (cGMP) are intracellular second messengers that vasodilate pul-
monary vessels. Increased levels of cyclic nucleotides lower [Ca
2+
]
i,
to relax PAs,
decrease pulmonary artery smooth muscle cells (PASMCs) proliferation, and
increase PASMC apoptosis (Koyama et al.
2001
; Rybalkin and Bornfeldt
1999
).
In PASMCs, cGMP exerts the majority of its actions through activation of protein
kinase G (PKG), whereas cAMP actions are mediated via protein kinase A (PKA)
and Epac [Exchange protein directly activated by cAMP; Epac-1 and Epac-2 are
known (Grandoch et al.
2010
)]: the relative importance of these mediators in the
vasodilation of the pulmonary circulation is currently under investigation. The PAs
from rats with experimental PAH and PASMCs isolated from PAH patients have
decreased cyclic nucleotide levels (MacLean et al.
1996
,
1997
; Murray et al.
2007
).
Many endogenous pulmonary vasodilators and therapies for PAH, such as nitric
oxide (NO) and stable analogues for prostacyclin, act by increasing the cellular
content of cGMP and cAMP, respectively. Increasing [cGMP]
i
, by addition of NO
or natriuretic peptides (atrial natriuretic peptide [ANP] and brain natriuretic peptide
[BNP]), reduces mPAP and PVR in experimental models of PAH; however, since
they require continuous delivery, such agents are difficult to use clinically (Baliga
et al.
2008
; Ghofrani et al.
2002
). Epoprostenol, treprostinil, and iloprost, which are
stable prostacyclin analogues, are approved to treat PAH; in severe PAH, iloprost
is effective in ~15% of patients (Ghofrani et al.
2002
; Olschewski et al.
2002
). The
therapeutic potential of prostacyclin analogues is hampered somewhat by issues
related to their delivery and the development of tolerance, hence new drugs that act
via increasing cyclic nucleotides are required.
