Skip to main content
SpringerLink
Log in

Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

An Erratum to this article was published on 25 January 2013

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. 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

    Article  PubMed  CAS  Google Scholar 

  2. 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

    Article  PubMed  CAS  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. 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

    Article  PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. Dobaczewski M, Frangogiannis NG (2009) Chemokines and cardiac fibrosis. Front Biosci 1:391–405

    Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. Frangogiannis NG (2004) The role of the chemokines in myocardial ischemia and reperfusion. Curr Vasc Pharmacol 2:163–174

    Article  PubMed  CAS  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. Guazzi M (2008) Sildenafil and phosphodiesterase-5 inhibitors for heart failure. Curr Heart Fail Rep 5:110–114

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  CAS  Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. 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

    Article  PubMed  Google Scholar 

  14. 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

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. 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

    Article  PubMed  CAS  Google Scholar 

  18. 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

    Article  PubMed  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  Google Scholar 

  21. Kuno K, Terashima Y, Matsushima K (1999) ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix. J Biol Chem 274:18821–18826

    Article  PubMed  CAS  Google Scholar 

  22. Landmesser U, Wollert KC, Drexler H (2009) Potential novel pharmacological therapies for myocardial remodelling. Cardiovasc Res 81:519–527. doi:10.1093/cvr/cvn317

    Article  PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. 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

    Article  PubMed  CAS  Google Scholar 

  25. 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

    Article  PubMed  CAS  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451:919–928. doi:10.1038/nature06798

    Article  PubMed  CAS  Google Scholar 

  30. 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

    Article  PubMed  CAS  Google Scholar 

  31. 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

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    PubMed  CAS  Google Scholar 

  34. 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

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. 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

    Article  PubMed  CAS  Google Scholar 

  38. 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

    Article  PubMed  CAS  Google Scholar 

  39. 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

    Article  PubMed  CAS  Google Scholar 

  40. 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

    Article  PubMed  Google Scholar 

  41. 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

    Article  PubMed  Google Scholar 

  42. 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

    Article  PubMed  Google Scholar 

  43. 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

    Article  PubMed  Google Scholar 

  44. 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

    Article  PubMed  CAS  Google Scholar 

  45. 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

    Article  PubMed  CAS  Google Scholar 

  46. 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

    Article  PubMed  CAS  Google Scholar 

  47. 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

    Article  PubMed  CAS  Google Scholar 

  48. 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

    Article  PubMed  CAS  Google Scholar 

  49. 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

    Article  PubMed  CAS  Google Scholar 

  50. 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

    Article  PubMed  Google Scholar 

  51. 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

    Article  PubMed  CAS  Google Scholar 

  52. 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Cardiology and Pneumology, Campus Benjamin Franklin (CBF), Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany

    Dirk Westermann, Peter Moritz Becher, Diana Lindner, Kostantinos Savvatis, Yu Xia, Matthias Fröhlich, Sebastian Hoffmann, Heinz-Peter Schultheiss & Carsten Tschöpe

  2. Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany

    Carsten Tschöpe

  3. DZHK (German Center for Cardiovascular Research), Berlin, Germany

    Carsten Tschöpe

Authors
  1. Dirk Westermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Moritz Becher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diana Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kostantinos Savvatis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Fröhlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sebastian Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heinz-Peter Schultheiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carsten Tschöpe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dirk Westermann.

Additional information

D. Westermann and P. M. Becher contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-012-0308-y

Keywords

Search

Navigation