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antiapoptotic effects and to protect against the development of contractile dysfunc-
tion in a mouse model of doxorubicin toxicity (Fisher et al.
2005
). While the
mechanisms of these effects in different models cannot be assumed to be identical,
they all appear to be dependent upon increases in intracellular cGMP content and the
consequent activation of protein kinase G (PKG) (Salloum et al.
2003
; Nagayama
et al.
2008
; Das et al.
2008
). Downstream signaling pathways involving calcineurin/
NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK have been implicated, and
evidence for the role of ERK phosphorylation and the induction of NO synthases and
Bcl-2 in the cardioprotective effects following ischemic injury is especially strong
(Takimoto et al.
2005
; Das et al.
2008
,
2009
). The vasodilatory action of PDE5
inhibitors could potentially release endogenous mediators of cardioprotection,
including adenosine and bradykinin, that trigger a signaling cascade that includes
the activation of protein kinase C and generation of NO by phosphorylation of eNOS
(Das et al.
2009
). NO activates guanylyl cyclase resulting in enhanced formation of
cGMP, which activates PKG (Das et al.
2008
; Salloum et al.
2009
).
One mechanism by which PKG induces cardioprotection is the ERK-dependent
opening of mitochondrial K
ATP
(mitoK
ATP
) channels (Das et al.
2009
). MitoK
ATP
channels feature prominently in the mechanism of cardioprotection because their
opening partially depolarizes mitochondrial membranes; this leads to an attenuation
of mitochondrial calcium accumulation during ischemia by decreasing the driving
force for Ca
2+
uptake (Liu et al.
1998
). Also, it has been shown that sildenafil causes
PKG-dependent phosphorylation and inactivation of glycogen synthase kinase 3ß
(GSK3
b
) in conjunction with an increase in Bcl-2/Bax ratio in cardiac myocytes
and in the intact heart (Das et al.
2008
). Inhibition of GSK-3
b
delays the opening of
the mitochondrial permeability transition (MPT) pore, a large-conductance pore in
the inner mitochondrial membrane that is opened under conditions associated with
ischemia/reperfusion, such as high matrix reactive oxygen species and high matrix
calcium (Juhaszova et al.
2004
). MitoK
ATP
opening also inhibits MPT and
decreases cell death through mechanism involving activation of mitochondrial
PKC-
e
(Garlid et al.
2009
). Moreover, pharmacological inhibitors of MPT have
been shown to reduce ischemia/reperfusion injury, suggesting that activation of
MPT might have a role in ischemia/reperfusion-mediated cell death (Lim et al.
2007
). Thus, the PKG-dependent opening of mitoK
ATP
channels or phosphorylation
of GSK-3
b
, with subsequent blocking of MPT, may have significant therapeutic
implications in protection against ischemia-reperfusion injury with sildenafil and
other PDE5 inhibitors (Fig.
4
).
5 Possible Involvement of PDE1 Inhibition in the Effects
of Sildenafil
The benefits of PDE5 inhibition in mouse models would be impressive if applicable
to the treatment of cardiac disease in humans, but there is reason to question whether
this is likely. In studies of cyclic nucleotide phosphodiesterases in normal human
