Abstract
Sildenafil inhibits cyclic GMP-specific phosphodiesterase type-5A (PDE5A) and can prevent cardiac hypertrophy and left ventricular (LV) dysfunction in mice subjected to severe pressure-overload. The pathophysiological role of sildenafil in adverse remodeling in the hypertensive heart after chronic renin–angiotensin aldosterone system stimulation is unknown. Therefore, we studied the efficacy of the PDE5A inhibitor sildenafil for treating advanced cardiac hypertrophy and LV remodeling due to angiotensin (Ang)II-induced heart failure (HF) in vivo. C57BL6/J mice were subjected to AngII-induced cardiac hypertrophy for 3 weeks and cardiac dysfunction, cardiac inflammatory stress response, adverse remodeling as well as apoptosis were documented. Mice were subsequently treated with sildenafil (100 mg/kg/day) or placebo with delay of 5 days for treating AngII infusion-induced adverse events. Compared to controls, AngII infusion resulted in impaired systolic (dP/dt max −46 %, SV −16 %, SW −43 %, E a +51 %, EF −37 %, CO −36 %; p < 0.05) and diastolic (dP/dt min −36 %, LV end diastolic pressure +73 %, Tau +21 %, stiffness constant β +74 %; p < 0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased inflammatory response was also indicated by an increase in immune cell infiltration and apoptosis. Treatment with sildenafil led to a significant improvement in systolic and diastolic LV performance. This effect was associated with less LV hypertrophy, remodeling, cardiac inflammation and apoptosis. PDE5A inhibition with sildenafil may provide a new treatment strategy for cardiac hypertrophy and adverse remodeling in the hypertensive heart.
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References
Abruzzo LV, Lee KY, Fuller A, Silverman A, Keating MJ, Medeiros LJ, Coombes KR (2005) Validation of oligonucleotide microarray data using microfluidic low-density arrays: a new statistical method to normalize real-time RT-PCR data. Biotechniques 38:785–792
Becher PM, Lindner D, Miteva K, Savvatis K, Zietsch C, Schmack B, Van Linthout S, Westermann D, Schultheiss HP, Tschope C (2012) Role of heart rate reduction in the prevention of experimental heart failure: comparison between if-channel blockade and beta-receptor blockade. Hypertension 59:949–957. doi:10.1161/HYPERTENSIONAHA.111.183913
Damas JK, Aukrust P, Ueland T, Odegaard A, Eiken HG, Gullestad L, Sejersted OM, Christensen G (2001) Monocyte chemoattractant protein-1 enhances and interleukin-10 suppresses the production of inflammatory cytokines in adult rat cardiomyocytes. Basic Res Cardiol 96:345–352
Devereux RB, Wachtell K, Gerdts E, Boman K, Nieminen MS, Papademetriou V, Rokkedal J, Harris K, Aurup P, Dahlof B (2004) Prognostic significance of left ventricular mass change during treatment of hypertension. JAMA 292:2350–2356. doi:10.1001/jama.292.19.2350
Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T, Michael LH, Rollins BJ, Entman ML, Frangogiannis NG (2005) CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res 96:881–889. doi:10.1161/01.RES.0000163017.13772.3a
Dobaczewski M, Frangogiannis NG (2009) Chemokines and cardiac fibrosis. Front Biosci 1:391–405
Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC (2005) Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicity. Circulation 111:1601–1610. doi:10.1161/01.CIR.0000160359.49478.C2
Frangogiannis NG (2004) The role of the chemokines in myocardial ischemia and reperfusion. Curr Vasc Pharmacol 2:163–174
Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A (2012) Chronic inhibition of cyclic GMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation 125:2323–2333. doi:10.1161/CIRCULATIONAHA.111.063412
Guazzi M (2008) Sildenafil and phosphodiesterase-5 inhibitors for heart failure. Curr Heart Fail Rep 5:110–114
Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD (2007) Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 50:2136–2144. doi:10.1016/j.jacc.2007.07.078
Hammoud L, Lu X, Lei M, Feng Q (2011) Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. Basic Res Cardiol 106:459–471. doi:10.1007/s00395-010-0147-7
Hassan MA, Ketat AF (2005) Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T. BMC Pharmacol 5:10. doi:10.1186/1471-2210-5-10
Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand JL, Cohen-Tervaert JW, Drexler H, Filippatos G, Felix SB, Gullestad L, Hilfiker-Kleiner D, Janssens S, Latini R, Neubauer G, Paulus WJ, Pieske B, Ponikowski P, Schroen B, Schultheiss HP, Tschope C, Van Bilsen M, Zannad F, McMurray J, Shah AM (2009) Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 11:119–129. doi:10.1093/eurjhf/hfn043
Hirata K, Adji A, Vlachopoulos C, O’Rourke MF (2005) Effect of sildenafil on cardiac performance in patients with heart failure. Am J Cardiol 96:1436–1440. doi:10.1016/j.amjcard.2005.06.091
Husberg C, Nygard S, Finsen AV, Damas JK, Frigessi A, Oie E, Waehre A, Gullestad L, Aukrust P, Yndestad A, Christensen G (2008) Cytokine expression profiling of the myocardium reveals a role for CX3CL1 (fractalkine) in heart failure. J Mol Cell Cardiol 45:261–269. doi:10.1016/j.yjmcc.2008.05.009
Kim KH, Kim YJ, Ohn JH, Yang J, Lee SE, Lee SW, Kim HK, Seo JW, Sohn DW (2012) Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity. Circulation 125:1390–1401. doi:10.1161/CIRCULATIONAHA.111.065300
Koka S, Xi L, Kukreja RC (2012) Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in type 2 diabetic hearts. Basic Res Cardiol 107:249. doi:10.1007/s00395-012-0249-5
Krupinski J, Turu MM, Martinez-Gonzalez J, Carvajal A, Juan-Babot JO, Iborra E, Slevin M, Rubio F, Badimon L (2006) Endogenous expression of C-reactive protein is increased in active (ulcerated noncomplicated) human carotid artery plaques. Stroke 37:1200–1204. doi:10.1161/01.STR.0000217386.37107.be
Kuhn C, Frank D, Dierck F, Oehl U, Krebs J, Will R, Lehmann LH, Backs J, Katus HA, Frey N (2012) Cardiac remodeling is not modulated by overexpression of muscle LIM protein (MLP). Basic Res Cardiol 107:262. doi:10.1007/s00395-012-0262-8
Kuno K, Terashima Y, Matsushima K (1999) ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix. J Biol Chem 274:18821–18826
Landmesser U, Wollert KC, Drexler H (2009) Potential novel pharmacological therapies for myocardial remodelling. Cardiovasc Res 81:519–527. doi:10.1093/cvr/cvn317
Leask A (2010) Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res 106:1675–1680. doi:10.1161/CIRCRESAHA.110.217737
Lee DI, Vahebi S, Tocchetti CG, Barouch LA, Solaro RJ, Takimoto E, Kass DA (2010) PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Basic Res Cardiol 105:337–347. doi:10.1007/s00395-010-0084-5
Lind T, Birch MA, McKie N (2006) Purification of an insect derived recombinant human ADAMTS-1 reveals novel gelatin (type I collagen) degrading activities. Mol Cell Biochem 281:95–102. doi:10.1007/s11010-006-0637-y
McKinsey TA, Kass DA (2007) Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface. Nat Rev Drug Discov 6:617–635. doi:10.1038/nrd2193
Miller CL, Cai Y, Oikawa M, Thomas T, Dostmann WR, Zaccolo M, Fujiwara K, Yan C (2011) Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol 106:1023–1039. doi:10.1007/s00395-011-0228-2
Mittaz L, Ricardo S, Martinez G, Kola I, Kelly DJ, Little MH, Hertzog PJ, Pritchard MA (2005) Neonatal calyceal dilation and renal fibrosis resulting from loss of Adamts-1 in mouse kidney is due to a developmental dysgenesis. Nephrol Dial Transplant 20:419–423. doi:10.1093/ndt/gfh603
Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451:919–928. doi:10.1038/nature06798
Nagayama T, Hsu S, Zhang M, Koitabashi N, Bedja D, Gabrielson KL, Takimoto E, Kass DA (2009) Sildenafil stops progressive chamber, cellular, and molecular remodeling and improves calcium handling and function in hearts with pre-existing advanced hypertrophy caused by pressure overload. J Am Coll Cardiol 53:207–215. doi:10.1016/j.jacc.2008.08.069
Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116:238–248. doi:10.1161/CIRCULATIONAHA.106.655266
Riad A, Bien S, Gratz M, Escher F, Westermann D, Heimesaat MM, Bereswill S, Krieg T, Felix SB, Schultheiss HP, Kroemer HK, Tschope C (2008) Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice. Eur J Heart Fail 10:233–243. doi:10.1016/j.ejheart.2008.01.004
Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y (2003) Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 111:959–972. doi:10.1172/JCI17115
Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi IZ, Hoke NN, Roy SK, Brown WR, Prabhakar S, Kukreja RC (2008) Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol 294:H1398–H1406. doi:10.1152/ajpheart.91438.2007
Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA (2012) Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol 59:9–15. doi:10.1016/j.jacc.2011.07.051
Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222. doi:10.1038/nm1175
Tamargo J, Lopez-Sendon J (2011) Novel therapeutic targets for the treatment of heart failure. Nat Rev Drug Discov 10:536–555. doi:10.1038/nrd3431
Tantini B, Manes A, Fiumana E, Pignatti C, Guarnieri C, Zannoli R, Branzi A, Galie N (2005) Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells. Basic Res Cardiol 100:131–138. doi:10.1007/s00395-004-0504-5
Tiede K, Melchior-Becker A, Fischer JW (2010) Transcriptional and posttranscriptional regulators of biglycan in cardiac fibroblasts. Basic Res Cardiol 105:99–108. doi:10.1007/s00395-009-0049-8
Toischer K, Kochhauser S, van Nguyen P, Leineweber K, Hasenfuss G, Kogler H (2012) Mechanical load-dependent cardiac ER stress in vitro and in vivo: effects of preload and afterload. FEBS Lett 586:1363–1369. doi:10.1016/j.febslet.2012.03.055
Toischer K, Rokita AG, Unsold B, Zhu W, Kararigas G, Sossalla S, Reuter SP, Becker A, Teucher N, Seidler T, Grebe C, Preuss L, Gupta SN, Schmidt K, Lehnart SE, Kruger M, Linke WA, Backs J, Regitz-Zagrosek V, Schafer K, Field LJ, Maier LS, Hasenfuss G (2010) Differential cardiac remodeling in preload versus afterload. Circulation 122:993–1003. doi:10.1161/CIRCULATIONAHA.110.943431
Volz HC, Laohachewin D, Seidel C, Lasitschka F, Keilbach K, Wienbrandt AR, Andrassy J, Bierhaus A, Kaya Z, Katus HA, Andrassy M (2012) S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-kappaB signaling. Basic Res Cardiol 107:250. doi:10.1007/s00395-012-0250-z
Wachtell K, Okin PM, Olsen MH, Dahlof B, Devereux RB, Ibsen H, Kjeldsen SE, Lindholm LH, Nieminen MS, Thygesen K (2007) Regression of electrocardiographic left ventricular hypertrophy during antihypertensive therapy and reduction in sudden cardiac death: the LIFE Study. Circulation 116:700–705. doi:10.1161/CIRCULATIONAHA.106.666594
Walker DK, Ackland MJ, James GC, Muirhead GJ, Rance DJ, Wastall P, Wright PA (1999) Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica 29:297–310. doi:10.1080/004982599238687
Watsky MA, Weber KT, Sun Y, Postlethwaite A (2010) New insights into the mechanism of fibroblast to myofibroblast transformation and associated pathologies. Int Rev Cell Mol Biol 282:165–192. doi:10.1016/S1937-6448(10)82004-0
Westermann D, Mersmann J, Melchior A, Freudenberger T, Petrik C, Schaefer L, Lullmann-Rauch R, Lettau O, Jacoby C, Schrader J, Brand-Herrmann SM, Young MF, Schultheiss HP, Levkau B, Baba HA, Unger T, Zacharowski K, Tschope C, Fischer JW (2008) Biglycan is required for adaptive remodeling after myocardial infarction. Circulation 117:1269–1276. doi:10.1161/CIRCULATIONAHA.107.714147
Westermann D, Riad A, Richter U, Jager S, Savvatis K, Schuchardt M, Bergmann N, Tolle M, Nagorsen D, Gotthardt M, Schultheiss HP, Tschope C (2009) Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol 104:499–509. doi:10.1007/s00395-009-0014-6
Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646. doi:10.2337/db06-1163
Westermann D, Savvatis K, Lindner D, Zietsch C, Becher PM, Hammer E, Heimesaat MM, Bereswill S, Volker U, Escher F, Riad A, Plendl J, Klingel K, Poller W, Schultheiss HP, Tschope C (2011) Reduced degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy. Circulation 124:2082–2093. doi:10.1161/CIRCULATIONAHA.111.035964
Westermann D, Walther T, Savvatis K, Escher F, Sobirey M, Riad A, Bader M, Schultheiss HP, Tschope C (2009) Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy. Diabetes 58:1373–1381. doi:10.2337/db08-0329
Yamamoto E, Kataoka K, Dong YF, Nakamura T, Fukuda M, Tokutomi Y, Matsuba S, Nako H, Nakagata N, Kaneko T, Ogawa H, Kim-Mitsuyama S (2009) Aliskiren enhances the protective effects of valsartan against cardiovascular and renal injury in endothelial nitric oxide synthase-deficient mice. Hypertension 54:633–638. doi:10.1161/HYPERTENSIONAHA.109.133884
Yin J, Kukucka M, Hoffmann J, Sterner-Kock A, Burhenne J, Haefeli WE, Kuppe H, Kuebler WM (2011) Sildenafil preserves lung endothelial function and prevents pulmonary vascular remodeling in a rat model of diastolic heart failure. Circ Heart Fail 4:198–206. doi:10.1161/CIRCHEARTFAILURE.110.957050
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We thank Kerstin Puhl, Georg Zingler, and Nadine Orrin for excellent technical assistance. This study was funded by the Deutsche Forschungsgesellschaft (SFB TR-19; A2, Z3).
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D. Westermann and P. M. Becher contributed equally to this work.
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Westermann, D., Becher, P.M., Lindner, D. et al. Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol 107, 308 (2012). https://doi.org/10.1007/s00395-012-0308-y
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DOI: https://doi.org/10.1007/s00395-012-0308-y