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3.1.2 Role of PDE1 in the Pulmonary Vasculature
Real-time PCR has demonstrated that a number of other PDEs are expressed in both
whole lung and human PASMCs (Fig.
1a
), although their roles in PAH have not
been fully investigated. By defining the expression of PDEs in human PASMCs
from normal subjects and patients with PAH, we obtained evidence for a biochemi-
cally and physiologically important role of PDE1 in PAH. PDE1 is encoded by
three separate genes with several splice variants: PDE1A, PDE1B (which is absent
in human PASMCs), and PDE1C, which hydrolyzes cAMP and cGMP with differ-
ent affinities and mediates, at least in part, the decrease in cAMP accumulation in
response to increases in [Ca
2+
]
i
(Goraya and Cooper
2005
; Miller et al.
2009
).
PDE1C has equal affinity for cAMP and cGMP and also hydrolyzes both at roughly
equal rate, whereas PDE1A has ~20-fold higher affinity for cGMP and PDE1B
has ~5-fold greater affinity for cGMP (Bender and Beavo
2006
). PDE1 may thus
provide “cross-talk” between the increased [Ca
2+
]
i
and decreased levels of cyclic
nucleotides that occur with PAH and unlike PDE5 or PDE3 inhibitors, inhibition of
PDE1 would increase both [cAMP]
i
and [cGMP]
i
, depending on the isoform that is
most abundant in that tissue.
We found an increase in the mRNA and protein expression of PDE1A and
PDE1C and increased total PDE1 activity in PASMCs isolated from patients with
both primary and secondary forms of PAH compared to PASMCs from controls,
and this increase contributed to decreased cAMP and cGMP levels and increased
proliferation of PAH-PASMCs (Murray et al.
2007
). Moreover, PDE1 inhibition
reduced proliferation in PAH-PASMCs more than did inhibition of PDE2 or PDE4,
decreased CCE by
50% and helped restore forskolin-and beraprost-induced
cAMP accumulation (Fig.
2a, b
). Expression of PDE1A, 1B, and 1C are detected
in PA from mice, rat, and lamb and increased expression is observed after develop-
ment of PAH (Evgenov et al.
2006
; Schermuly et al.
2007
). Figure
3
demonstrates
that PDE1 expression and activity are increased in the monocrotaline-treated rat
lung, providing a further rationale for targeting PDE1, in particular PDE1C, in
PAH.
The data obtained from animal models that implicate a role for PDE1 in PAH
must be interpreted with caution. In human SMCs, unlike SMCs from other species,
PDE1C is more dependent on calmodulin-stimulated cAMP hydrolysis and an
increase in PDE1C is associated with SMC proliferation (Rybalkin and Bornfeldt
1999
; Rybalkin et al.
1997
,
2002
). Due to the marked differences in expression,
activities, and function of PDE1 isoforms in SMCs from different species, animal
models of PAH may not be appropriate to study PDE1 and thus, not show the full
therapeutic potential of PDE1 inhibitors. Even so, in perfused rat lung preparations,
administration of the PDE1 inhibitor vinpocetine attenuates acute hypoxic vaso-
constriction and PDE1 inhibitors augment the therapeutic efficacy of inhaled NO
and iloprost in animal models of PAH: PDE1 inhibitors applied at subthreshold
doses enhanced iloprost-induced decrease in mPAP to a similar degree as a
PDE3 inhibitor and did not decrease systemic pressure (Evgenov et al.
2006
;
Phillips et al.
2005
; Schermuly et al.
2005
; Wagner et al.
1997
). The PDE inhibitor
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