Biology Reference
In-Depth Information
Fig. 4 Schematic of some mechanisms that contribute to the vasodilatory, antiproliferative, and
apoptotic actions of cAMP and cGMP (by PDE inhibition) in PASMCs. The effects of cyclic
nucleotides are mediated by PKG and PKA activation, potassium channel opening, and a decrease
in intracellular [Ca
2+
] that leads to phosphorylation of a number of downstream proteins, decrease
in ROS and altered activity of transcription factors. Further details are given in the text
expression has been shown to contribute to a reduced response (“tolerance”) to
drugs that increase NO; the PDE1 inhibitor vinpocetine partially restores sensitivity
of the vasculature to nitroglycerin (Kim et al.
2001
). Moreover, in vascular SMCs,
the nuclear localization of PDE1A can, by decreasing cGMP, protect the cells from
apoptosis (Nagel et al.
2006
). PDE1C is present in proliferating aortic SMCs but
absent in intact human thoracic aorta and not expressed in contractile/quiescent
cells, findings that suggest PDE1C contributes to the proliferative phenotype of
vascular SMCs (Rybalkin and Bornfeldt
1999
; Rybalkin et al.
1997
,
2002
); PDE1C
has also been shown to associate with chromatin, which may contribute to SMC
replication (Dolci et al.
2006
). These data suggest that PDE1 isoforms regulate
smooth muscle function and may be useful targets for the treatment of diseases with
excess smooth muscle cell proliferation. Such ideas are consistent with our data
showing that treatment with PDE1C-siRNA inhibits proliferation of PASMCs, in
particular cells from PAH patients (Murray et al.
2007
). Figure
4
shows a schematic
of the signalling pathways and mediators that may contribute to the vasodilatory,
antiproliferative and apoptotic actions of PDE inhibitors in PASMCs and hence
their benefical effects in PAH.
3.2 Role of PDEs in the Right Ventricular Hypertrophy
Much of the research in PAH focuses on developing effective treatments to
vasodilate and reverse the remodeling of the PA and thereby reduce mPAP.
