View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 59, No. 22, 2012 © 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2011.09.086 STATE-OF-THE-ART PAPER Cyclic Guanosine Monophosphate Signaling and Phosphodiesterase-5 Inhibitors in Cardioprotection Rakesh C. Kukreja, PHD, Fadi N. Salloum, PHD, Anindita Das, PHD Richmond, Virginia Cyclic guanosine monophosphate (cGMP) is an important intracellular second messenger that mediates multiple tissue and cellular responses. The cGMP pathway is a key element in the pathophysiology of the heart and its modulation by drugs such as phosphodiesterase (PDE)-5 inhibitors and guanylate cyclase activators may repre- sent a promising therapeutic approach for acute myocardial infarction, cardiac hypertrophy, heart failure, and doxorubicin cardiotoxicity in patients. In addition, PDE-5 inhibitors may prove to be innovative therapeutic agents for enhancing the chemosensitivity of doxorubicin while providing concurrent cardiac benefit. (J Am Coll Cardiol 2012;59:1921–7) © 2012 by the American College of Cardiology Foundation Cyclic guanosine monophosphate (cGMP) is a critical of cyclic adenosine monophosphate (cAMP) and/or cGMP intracellular second messenger regulating fundamental to produce the corresponding 5’ nucleotide. Currently, 21 physiological processes in the myocardium, from acute PDE genes have been cloned and are classified into 11 contraction/relaxation to chronic gene expression, cell families according to their sequence of homology, biochem- growth, and apoptosis. Several studies have shown that ical, and pharmacological properties (6). The PDEs vary in cGMP inhibits hypertrophy, reduces ischemia-reperfusion their substrate specificity for cAMP and cGMP: PDE-5, (I/R) injury, and regulates contractile function and cardiac PDE-6, and PDE-9 are specific for cGMP; PDE-4, remodeling (1–3). cGMP is generated from the cytosolic PDE-7, and PDE-8 are specific for cAMP; and PDE-1, purine nucleotide guanosine triphosphate by guanylyl cy- PDE-2, PDE-3, PDE-10, and PDE-11 have mixed spec- 2ϩ 2ϩ lases (GCs) using Mg or Mn as cofactors. Two ificity for cAMP/cGMP (7). PDE-5 selectively hydrolyzes isoforms of GCs exist in vertebrate cells and tissues: a nitric cGMP, and its inhibition increases cGMP bioavailability. oxide (NO)-sensitive cytosolic or soluble guanylyl cyclase The abundance of PDE-5 in smooth muscles and its role in (sGC) and natriuretic peptide (NP)-activated plasma mem- regulating their contractile tone has made PDE-5 an brane bound, particulate guanylyl cyclase (pGC). Once important drug target for the treatment of erectile dysfunc- produced, the effects of cGMP occur through 3 main groups tion (6), leading to the development of potent PDE-5 of cellular target molecules: cyclic guanosine monophos- inhibitors, such as sildenafil (Viagra and Revatio, Pfizer, phate–dependent protein kinases (PKGs), cGMP-gated New York, New York), vardenafil (Levitra, Bayer Schering cation channels, and phosphodiesterases (PDEs). cGMP Pharma AG, Leverkusen, Germany), and tadalafil (Cialis positively regulates PKG but inhibits/activates PDEs, and Adcirca, Eli Lilly Canada Inc., Toronto, Ontario, which are predominant in the cardiovascular system (4,5). Canada). Revatio and Adcirca have also been approved for This paper reviews many of the latest findings on cGMP related to the cardioprotection. the treatment of pulmonary hypertension. Earlier studies found that PDE-5 is not present in normal cardiomyocytes Regulation of cGMP by PDEs (8,9), although later investigations revealed its expression in canine (10), mouse cardiomyocytes (1,11,12), and human The cGMP pool in the cell is tightly controlled by PDEs, heart (13,14). PDE-5 expression is increased in hypertro- which specifically cleave the 3=,5=-cyclic phosphate moiety phic human right ventricle, as well as failing left ventricular tissue (13–15). A gene silencing model also confirmed From the Pauley Heart Center, Division of Cardiology, Department of Internal PDE-5 protein expression (16), whereas a recent report still Medicine, Virginia Commonwealth University, Richmond, Virginia. This study was questioned its presence in adult mouse cardiac myocytes supported by grants from the National Institutes of Health (HL51045, HL79424, (17). Because cGMP-hydrolytic activity is also attributable and HL93685) to Dr. Kukreja and a National Scientist Development Grant from the American Heart Association (10SDG3770011) to Dr. Salloum. The authors have to PDE-1 and PDE-3, Vandeput et al. (14) suggested that reported that they have no relationships relevant to the contents of this paper to the effects of sildenafil on cGMP hydrolysis were due to disclose. Manuscript received July 6, 2011; revised manuscript received September 15, 2011, inhibition of both PDE-5 and PDE-1 in the left ventricles accepted September 20, 2011. of normal and failing mouse hearts. 1922 Kukreja et al. JACC Vol. 59, No. 22, 2012 cGMP Signaling in Cardioprotection May 29, 2012:1921–7 Abbreviations cGMP in Pre- and concentrations. ANP is primarily stored in atrial granules and and Acronyms Post-Conditioning secreted in response to atrial stretch. BNP is also in atrial granules but is found in the highest level in ventricles of -atrial natriuretic NO triggers various physiologi ؍ ANP peptide stressed hearts (28). C-type NP is found at lower concentration cal responses by binding and ac- in vascular endothelium and is present in higher concentration B-type natriuretic tivating sGC to produce cGMP ؍ BNP peptide in chondrocytes where it stimulates long bone growth (29). In from guanosine triphosphate ,the cardiovascular system, NPs exhibit growth suppressive ؍ cAMP cyclic adenosine (18). NO-cGMP-PKG signal- monophosphate antiproliferative, and antihypertrophic actions on vascular ing pathway is involved in the .(cyclic guanosine smooth muscle cells, cardiomyocytes, and fibroblasts (30 ؍ cGMP cardioprotective action in I/R in- monophosphate ANP/BNP exert myocardial protective effects against I/R jury as a survival signal (19,20). doxorubicin injury through a cGMP-PKG–dependent modulation ؍ DOX In cardiomyocytes, cGMP re- of mitoK channels (31). ANP also protects against ؍ DMD Duchenne muscular duced the effects of myocyte stun- ATP dystrophy reoxygenation-induced hypercontracture in cardiomyo- ning after simulated I/R (21). The -guanylyl cyclase cytes by stimulating cGMP synthesis (32). Administra ؍ GC NO donor S-nitroso-N-acetyl- tion of ANP at reperfusion protected against I/R injury ؍ I/R ischemia-reperfusion L,L-penicillamine mimicked the -dystrophin-deficient (33,34) and exerted antiapoptotic effects in rat cardiomy ؍ mdx pre-conditioning–like effect by ocytes through cGMP-PKG and by inducing phospha- myocardial infarction ؍ MI inducing cGMP (22). Moreover, tidylinositol 3-kinase-protein kinase B (PI3K/AKT) sig- ؍ mitoKATP mitochondrial the activation of the NO/cGMP/ naling (35). cGMP analogue, 8-Br-cGMP, or elevation KATP PKG pathway inhibited the ele- ϩ of intracellular cGMP concentration via the sGC activator nitric oxide 2 ؍ NO vation of intracellular Ca con- NO or BNP exerted cardioprotective effects through PKG .(nitric oxide centrations by phosphorylating activation (36 ؍ NOS synthase target proteins responsible for in- ϩ Cinaciguat (BAY 58-2667) activates sGC independent of 2 ؍ NP natriuretic peptide tracellular Ca homeostasis during NO (37). This drug preferentially activates sGC when the phosphodiesterase I/R injury in Chinese hamster ؍ PDE .(particulate guanylyl ovary cells (23 ؍ pGC cyclase Ischemic pre-conditioning rap- cyclic guanosine idly increased cGMP levels via ؍ PKG monophosphate–dependent sGC during ischemia, leading to protein kinases delayed protective effect (24 h -soluble guanylyl later) against myocardial stun ؍ sGC cyclase ning and infarction in conscious rabbits (24). Bradykinin, one of the triggers of pre-conditioning, caused receptor-mediated production of NO resulting in cGMP production, activation of PKG, and opening of mitochondrial KATP (mitoKATP) chan- nel in rabbit heart and cardiomyocytes (25). Opening of mitoKATP channels causes partial compensation of the mem- brane potential, which enables additional protons to be ϩ pumped out to form a H electrochemical gradient for both ϩ adenosine triphosphate synthesis and Ca2 transport (26). The cGMP/PKG pathway also confers ischemic post-conditioning protection in part by delaying normalization of pH during ϩ reperfusion, probably via PKG-dependent inhibition of Na / ϩ H -exchanger in rat heart (27). cGMP Modulatory Drugs for Cardioprotection cGMP modulatory drugs induce cardioprotective effect Figure 1 Myocardial Protection by Up-Regulation of cGMP through PKG as outlined in Figure 1. NPs exert biological Cardioprotective modalities including pre-conditioning, post-conditioning, atrial effects by binding to membrane-associated pGC. Atrial natriuretic peptide (ANP)/B-type natriuretic peptide (BNP), nitric oxide (NO) natriuretic peptide (ANP), B-type natriuretic peptide donors, and Cinaciguat generate cyclic guanosine monophosphate (cGMP) (BNP), and C-type NP are 3 structurally related, but through activation of soluble guanylyl cyclase (sGC)/particulate guanylyl cyclase (pGC). cGMP exerts cardioprotective effects against ischemia/reperfusion injury genetically distinct, signaling molecules that regulate the through activation of cyclic