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approach by targeting both the vascular and the immune aspects of the disease
(Fig.
1
) (Izikki et al.
2009
). In the monocrotaline-treated rat, in which inflammation
is key to the development of PAH, the PDE3/PDE4 inhibitor tolafentrine alone or
together with iloprost reverses the increase in mPAP, RV hypertrophy, and pulmo-
nary vascular remodeling in fully established PAH and inhibits the associated
increase in activity of MMP-2 and MMP-9: although systemic arterial pressure
decreases on acute exposure to tolafentrine, this is not sustained (Schermuly
et al.
2004
). In parallel, the dual PDE3/PDE4 inhibitor pumafentrine, which
dose-dependently increases cAMP and decreases proliferation in isolated human
PASMCs, significantly reversed the muscularization, media hypertrophy, and the
decrease in the lumen of the small PAs, suggesting that this inhibitor is proapoptotic
(Dony et al.
2008
). These data imply that targeting PDE4/PDE3 would be beneficial
for PAH. However, due to the dose-limiting side effects of PDE3 and PDE4
inhibitors, more research is required to determine whether such drugs will be
clinically useful. Because PDE7 is also highly expressed in immune cells and
upregulated in PAH-PASMCs, targeting of this PDE could be a novel approach
in the treatment of PAH and merits further investigation.
4 Conclusion and the Future of PDEs in PAH
PAH is a complex, multifactorial disease with no single cause and thus, it is
unlikely that one drug will prove to be therapeutically beneficial for all patients.
Nevertheless, the evidence reviewed here strongly implicates a key role for PDEs
in the increased mPAP and remodeling of the PA that is associated with PAH. The
clinical success of PDE5 inhibitors (e.g., sildenafil) in different forms of PAH
implies that PDE5 expression and activity contribute to the pathophysiology of
PAH. In order to more clearly determine the role of other PDEs, in particular PDE1,
selective inhibitors are needed; the development of inhibitors that can target
specific PDE isoforms has the potential to provide therapeutic utility by providing
efficacy but decreasing side effects.
Since mRNA for PDE1A, PDE1C, PDE3A, PDE3B, and PDE5A are all upre-
gulated in PAH, their regulation in this disease likely occurs at the level of
transcription (Fig.
1b
) (Murray et al.
2007
). However, relatively limited informa-
tion is available regarding the transcriptional control of specific PDEs. We have
hypothesized that the increase in PDE3A expression with PAH is attributable to
PKA-dependent CREB activation, through an initial accumulation of cAMP to
protect the pulmonary circulation from insult and to try and restore normal tone
(Murray et al.
2002
). Studies have suggested that the increase in PDE5A mRNA
occurs via increased NF
k
B activation; mapping the promoter of PDE5A identified a
number of Sp1-, AP-1, NF
k
B-, and CRE-binding sites (Lin et al.
2001a
,
b
; Murray
et al.
2002
; Pyne et al.
2007
). Further data show that PDE5A expression is
upregulated via Ang-II-mediated ERK1/2-activation and increased superoxide
derived from NOX; however, no transcription factors were directly implicated
