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Am J Physiol Heart Circ Physiol
296:1209-1210, 2009. First published Apr 3, 2009;
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AJP - Heart and Circulatory Physiology
This information is current as of July 31, 2009 .
AJP - Heart and Circulatory Physiology
publishes original investigations on the physiology of the heart, blood vessels, and
lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the
intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American
Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2005 by the American Physiological Society.
Am J Physiol Heart Circ Physiol
296: H1209–H1210, 2009;doi:10.1152/ajpheart.00298.2009.
How does Viagra protect the ischemic heart?
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and CellularBiochemistry, the Ohio State University College of Medicine, Columbus, Ohio
SILDENAFIL, BETTER KNOWN AS Viagra, is the first oral medicine
Indeed, Das et al. (2) showed that inhibiting ERK1/2 with
approved for treating erectile dysfunction. Interestingly, silde-
PD98059 eradicated both acute and delayed protective effects
nafil was originally intended for coronary heart disease. But the
of sildenafil on postischemic hearts. It should be mentioned
initial result from the clinical study on its effectiveness easing
that it is not uncommon that small-molecule kinase inhibitors
coronary syndrome was gloomy. On the other hand, patients
exhibit off-target effects. But PD98059 has been extensively
reported a side effect: sildenafil may enhance erectile function.
scrutinized and found to be rather selective to MAPK kinase 1,
This side effect quickly took the place of its primary applica-
the upstream kinase of ERK1/2 (4). Further studies revealed
tion, and sildenafil grew to be a multibillion dollar blockbuster
that the sildenafil-elicited protective events such as eNOS/
in the drug market. However, the story does not just end there.
iNOS and Bcl-2 upregulation can all be blocked by PD98059.
New excitement and surprises keep emerging from the study
On the other hand, PD98059 had no effect on the PKG
on sildenafil. Over the past few years, sildenafil was found to
activation in sildenafil-treated hearts. These findings establish
protect hearts against ischemia-reperfusion injury (3, 8). Stud-
ERK1/2 as a key mediator that relays the signal of sildenafil-
ies also showed that sildenafil suppresses cardiac hypertrophy
induced PKG activation to other downstream pathways.
and improves heart function in mice exposed to chronic pres-
Das et al. (2) have compiled a schematic diagram to depict
sure overload (9). Although a variety of mechanisms have been
the signaling transduction process underlying the protective
implicated in the effect of sildenafil, the signaling process that
effect of sildenafil on ischemic hearts. Although this scheme is
mediates the cardioprotection of sildenafil in ischemic hearts
certainly subject to constant modification, it does point out
has not been fully understood. Das et al. (2) provide compel-
many directions of future research. For example, how does
ling evidence that ERK1/2 may be the key mediator that
PKG activate ERK1/2? Is this a direct effect or a process
bridges cGMP-dependent protein kinase (PKG) to various
involving other mediators? How does ERK1/2 activation en-
downstream protective mechanisms in the action of sildenafil.
hance iNOS and eNOS expressions? iNOS expression isknown to be primarily governed by NK-B and signal trans-
Sildenafil is a specific inhibitor of phosphodiesterase-5 (PDE-
ducer and activators of transcription 1 (STAT1). Although
5), an enzyme responsible for breaking down cGMP. By inhib-
many studies have shown that ERK1/2 may mediate cytokine-
iting PDE-5, sildenafil raises cytosolic cGMP concentrations
induced STAT1 activation, whether ERK1/2 initiates iNOS
leading to PKG activation. Since Kukreja and colleagues (8)
gene expressions via STAT1 still needs to be examined in the
first reported that sildenafil protected hearts against ischemic
context of sildenafil-treated hearts. There are studies showing that
injury in a rabbit ischemia-reperfusion model, the beneficial
in lysophosphatidylcholine-treated endothelial cells, ERK1/2 ac-
effect of sildenafil on ischemic hearts has been confirmed by
tivation may stimulate the binding of Sp1 to the eNOS promoter,
other groups on different animal species. Sildenafil induces
leading to increased eNOS expressions (1). Whether Sp1 is
both acute and delayed protection to the hearts subjected to
involved in eNOS upregulation in hearts after sildenafil treat-
ischemia and reperfusion. A number of mechanisms have been
ment is an interesting question for future investigation. Fur-
reported to account for the effect of sildenafil on ischemic
thermore, the proposed mechanism may provide a plausible
hearts. These include upregulated endothelial nitric oxide syn-
explanation for the delayed cardioprotection. On the other
thase/inducible nitric oxide synthase (eNOS/iNOS, respec-
hand, the acute cardioprotection of sildenafil is clearly unre-
tively) expressions, PKC activation, induction of antiapoptotic
lated to the increases in eNOS/iNOS expression. Further stud-
protein Bcl-2, opening of mitochondrial ATP-sensitive Kϩ
ies are needed to elucidate how sildenafil-induced ERK1/2
channels (KATP), etc. In an earlier study published by the same
activation leads to cardioprotection in the acute setting.
group, Das et al. (3) used pharmacological as well as gene
Another intriguing finding from this study is that a single
knockdown approaches confirming that PKG activation was nec-
injection of sildenafil resulted in prolonged inhibition of GSK-
essary for the cardioprotective effects of sildenafil. However, an
3␤. ERK1/2 inhibition significantly reversed sildenafil-induced
important question remains regarding how PKG activation is
GSK-3␤ inhibition. Das et al. (2) speculate that GSK-3␤
linked to other downstream protective mechanisms. These authors
inhibition may be involved in the delayed cardioprotection by
previously found that sildenafil induced ERK1/2 activation in a
sildenafil. Indeed, the inactivation of GSK-3␤ has been pro-
PKG-dependent manner (3). ERK1/2 belongs to a family of
posed as a common target of various protective signals in
MAPKs, which have been shown to play crucial roles in cell
ischemia-initiated preconditioning (6), but how GSK-3␤ inhi-
survival and ischemic preconditioning. Thus ERK1/2 appears to
bition induces protection to ischemic hearts remains incom-
be an ideal candidate to transmit the signal of PKG activation to
pletely understood. The mitochondrial permeability transition
other pathways in sildenafil-treated hearts.
pore (mPTP) has been reported to be the target of GSK-3␤.
GSK-3␤ inhibition reduces mPTP openings, and this gives riseto cell protection. In addition, recent studies demonstrated that
Address for reprint requests and other correspondence: Y. Xia, 605 DHLRI,
the Ohio State Univ., 473 West 12th Ave., Columbus, OH 43210 (e-mail:
␤ profoundly regulates progenitor cell proliferation. In
fact, small molecule GSK-3 inhibitors have been used to
0363-6135/09 $8.00 Copyright 2009 the American Physiological Society
maintain the pluripotency of stem cells (5). Numerous studies
have reported that progenitor cell infusions protect the heart
1. Cieslik K, Abrams CS, Wu KK.
Up-regulation of endothelial nitric-
from ischemic injury. We can hypothesize that sildenafil-
oxide synthase promoter by the phosphatidylinositol 3-kinase gamma/
induced GSK-3␤ inhibition may promote progenitor cell pro-
Janus kinase 2/MEK-1-dependent pathway. J Biol Chem
liferation. It will be of significant interest to investigate
whether sildenafil affects progenitor cell proliferation, and if
2. Das A, Salloum FN, Xi L, Rao YJ, Kukreja RC.
mediates sildenafil-induced myocardial protection against ischemia-reper-
so, how this is related to its delayed cardioprotective effect.
fusion injury in mice. Am J Physiol Heart Circ Physiol
(March 13, 2009).
It appears that after the unintended effect of sildenafil took
over the center stage of its application for so many years, the
3. Das A, Xi L, Kukreja RC.
Protein kinase G-dependent cardioprotective
originally sought cardiovascular benefit may eventually mate-
mechanism of phosphodiesterase-5 inhibition involves phosphorylation of
rialize. It is noteworthy that the doses of sildenafil used in the
ERK and GSK3beta. J Biol Chem
283: 29572–29585, 2008.
cardioprotection study are comparable to those for treating
4. Davies SP, Reddy H, Caivano M, Cohen P.
Specificity and mechanism of
action of some commonly used protein kinase inhibitors. Biochem J
erectile dysfunction (2). Since sildenafil has been widely pre-
scribed for over a decade, a retrospective clinical study on the
5. Doble BW, Woodgett JR.
Exploring pluripotency with chemical genetics.
effect of sildenafil on myocardial infarction is warranted. In
Cell Stem Cell
4: 98 –100, 2009.
fact, there was a study reporting that the incidence of myocar-
6. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman
dial infarction was seemingly lower among the sildenafil users
BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ.
(7). Certainly, these results need to be further verified. The study
synthase kinase-3beta mediates convergence of protection signaling toinhibit the mitochondrial permeability transition pore. J Clin Invest
by Das et al. (2) was conducted on male mice. It remains to be
seen whether female animals can similarly benefit from sildenafil
7. Kontaras K, Varnavas V, Kyriakides ZS.
Does sildenafil cause myocar-
against ischemia-reperfusion injury. Unfortunately, retrospective
dial infarction or sudden cardiac death? Am J Cardiovasc Drugs
studies will unlikely provide an answer to this question since
female sildenafil users are scarce. Thus a carefully controlled
8. Ockaili R, Salloum F, Hawkins J, Kukreja RC.
clinical trial on the effect of sildenafil on patients, both men and
induces powerful cardioprotective effect via opening of mitochondrial KATPchannels in rabbits. Am J Physiol Heart Circ Physiol
women, with ischemic heart disease deserves priority.
9. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER,
Bedja D, Gabrielson KL, Wang Y, Kass DA.
Chronic inhibition of cyclic
This work was supported by National Heart, Lung, and Blood Institute
GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat
AJP-Heart Circ Physiol
• VOL 296 • MAY 2009 • www.ajpheart.org
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