Biology Reference
In-Depth Information
the understanding that the reduction in cAMP-mediated signaling in failing hearts,
despite its negative effect on myocardial contractility, confers some advantages that
are forfeited when cAMP-raising therapeutic strategies are implemented (for
review, see (Movsesian and Bristow
2005
)). Most of the studies showing increased
mortality with PDE3 inhibition were carried out before the implantation of cardiac
defibrillators in patients with dilated cardiomyopathy became standard therapy, and
it is possible that these adverse effects would be less of an issue in patients with
defibrillators. In addition, several studies suggest that the concomitant administra-
tion of antiarrhythmic agents can improve clinical outcomes in patients receiving
long-term PDE3 inhibition, but this has not, to our knowledge, been tested in a
large, randomized prospective trial (Nanas et al.
2004
; Drakos et al.
2009
).
The specific molecular mechanisms to which the inotropic and proarrhythmic
consequences of PDE3 inhibition are attributable have not been established with
certainty, but inotropic effects are likely to result from increases in the phosphory-
lation of several membrane-bound substrates of protein kinase A. Phosphorylation
of L-type Ca
2+
channels increases Ca
2+
influx during systole (Sculptoreanu et al.
1993
); phosphorylation of ryanodine-sensitive Ca
2+
channels increases Ca
2+
release
by the sarcoplasmic reticulum (Takasago et al.
1989
); and phosphorylation of
phospholamban blocks its inhibitory interaction with SERCA2, the Ca
2+
-transporting
ATPase of the sarcoplasmic reticulum, resulting in an increase in Ca
2+
accumula-
tion during diastole (Simmerman and Jones
1998
). These actions increase the
amplitude of intracellular Ca
2+
transients, which are attenuated in dilated cardio-
myopathy (Beuckelmann et al.
1992
). Studies in animal models suggest that the
phosphorylation of phospholamban may be the most therapeutically relevant of
these mechanisms. Depletion of phospholamban and expression of a nonfunctional
mutant form of the protein - which mimics the stimulation of SERCA2 activity
seen with phospholamban phosphorylation - increase contractility in cultured
cardiac myocytes, while germline ablation of phospholamban, knockdown with
antisense RNA and expression of anti-phospholamban antibody-derived proteins
improve contractile function and prevent pathologic remodeling (Minamisawa et al.
1999
; He et al.
1999
; Hoshijima et al.
2002
; Iwanaga et al.
2004
; Eizema et al.
2000
;
Watanabe et al.
2004
; Suckau et al.
2009
; Dieterle et al.
2005
; Meyer et al.
2004
).
Less is known about the molecular mechanisms responsible for the adverse long-
term effects of PDE3 inhibition. It is not clear whether the increase in arrhythmias
and sudden death observed in clinical trials is due to proarrhythmic consequences of
the increase in intracellular Ca
2+
cycling or to a cAMP-mediated acceleration
of pathologic remodeling. The reductions in sudden death seen in clinical trials of
angiotensin-converting enzyme inhibitors, isosorbide dinitrate/hydralazine, and
b
-adrenergic receptor antagonists may be evidence for the latter explanation
(Amsallem et al.
2005
). Pathologic remodeling has been associated with an increase
in apoptosis in human disease and in animal models (for review, see Dorn
2009
).
Recent studies in rats suggest that PDE3 inhibition has proapoptotic consequences
associated with a sustained increase in the expression of inducible cAMP early
repressors (“ICERs”), and that this effect is mediated through the phosphorylation
of the transcription factor CREB by PKA (Ding et al.
2005a
,
b
; Yan et al.
2007
).
