Yong Xia
Am J Physiol Heart Circ Physiol 296:1209-1210, 2009. First published Apr 3, 2009;
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This article cites 9 articles, 4 of which you can access free at: including high-resolution figures, can be found at: AJP - Heart and Circulatory Physiology
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Am J Physiol Heart Circ Physiol 296: H1209–H1210, 2009;doi:10.1152/ajpheart.00298.2009.
Editorial Focus
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 Editorial Focus
maintain the pluripotency of stem cells (5). Numerous studies REFERENCES
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 276: 1211– 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. ERK phosphorylation
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 351: 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. Glycogen
(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 113: 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 8: 1–7, 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. Sildenafil (Viagra)
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 283: H1263–H1269, women, with ischemic heart disease deserves priority.
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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 •


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