Skip to main content
Log in

Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Background

Ticagrelor inhibits the equilibrative-nucleoside-transporter-1 and thereby, adenosine cell re-uptake. Ticagrelor limits infarct size (IS) in non-diabetic rats and the effect is adenosine-dependent. Statins, via ecto-5′-nucleotidase activation, also increase adenosine levels and limit IS.

Hypothesis

Ticagrelor and rosuvastatin have additive effects on myocardial adenosine levels, and therefore, on IS and post-reperfusion activation of the NLRP3-inflammasome.

Methods

Diabetic ZDF rats received via oral gavage; water (control), ticagrelor (150 mg/kg/d), prasugrel (7.5 mg/kg/d), rosuvastatin (5 mg/kg/d), ticagrelor + rosuvastatin and prasugrel + rosuvastatin for 3d. On day 4, rats underwent 30 min coronary artery occlusion and 24 h of reperfusion. Two additional groups received, ticagrelor + rosuvastatin or water in combination with CGS15943 (CGS, an adenosine receptor antagonist, 10 mg/kg i.p. 1 h before ischemia).

Results

Both ticagrelor and rosuvastatin increased myocardial adenosine levels with an additive effect of the combination whereas prasugrel had no effect. Similarly, both ticagrelor and rosuvastatin significantly reduced IS with an additive effect of the combination whereas prasugrel had no effect. The effect on IS was adenosine dependent as CGS15943 reversed the effect of ticagrelor + rosuvastatin. The ischemia-reperfusion injury increased myocardial mRNA levels of NLRP3, ASC, IL-1β and IL-6. Ticagrelor and rosuvastatin, but not prasugrel, significantly decreased these pro-inflammatory mediators with a trend to an additive effect of the combination. The combination also increased the levels of anti-inflammatory 15-epilipoxin A4.

Conclusions

Ticagrelor and rosuvastatin when given in combination have an additive effect on local myocardial adenosine levels in the setting of ischemia reperfusion. This translates into an additive cardioprotective effect mediated by adenosine-induced effects including downregulation of pro- but upregulation of anti-inflammatory mediators.

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

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Adameova A, Harcarova A, Matejikova J, Pancza D, Kuzelova M, Carnicka S, Svec P, Bartekova M, Styk J, Ravingerova T. Simvastatin alleviates myocardial contractile dysfunction and lethal ischemic injury in rat heart independent of cholesterol-lowering effects. Physiol Res. 2009;58:449–54.

    CAS  PubMed  Google Scholar 

  2. Altaf A, Qu P, Zhao Y, Wang H, Lou D, Niu N. NLRP3 inflammasome in peripheral blood monocytes of acute coronary syndrome patients and its relationship with statins. Coron Artery Dis. 2015;26:409–21.

    Article  PubMed  Google Scholar 

  3. Amsterdam EA, Wenger NK, Brindis RG, Casey Jr DE, Ganiats TG, Holmes Jr DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC guideline for the Management of Patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;64:e139–228.

    Article  PubMed  Google Scholar 

  4. Armstrong D, Summers C, Ewart L, Nylander S, Sidaway JE, van Giezen JJ. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19:209–19.

    Article  CAS  PubMed  Google Scholar 

  5. Atar S, Ye Y, Lin Y, Freeberg SY, Nishi SP, Rosanio S, Huang MH, Uretsky BF, Perez-Polo JR, Birnbaum Y. Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2. Am J Physiol Heart Circ Physiol. 2006;290:H1960–8.

    Article  CAS  PubMed  Google Scholar 

  6. Berger JS. Aspirin, clopidogrel, and ticagrelor in acute coronary syndromes. Am J Cardiol. 2013;112:737–45.

    Article  CAS  PubMed  Google Scholar 

  7. Birnbaum GD, Birnbaum I, Ye Y, Birnbaum Y. Statin-induced cardioprotection against ischemia-reperfusion injury: potential drug-drug interactions. Lesson to be learnt by translating results from animal models to the clinical settings. Cardiovasc Drugs Ther. 2015;29:461–7.

    Article  CAS  PubMed  Google Scholar 

  8. Birnbaum Y, Lin Y, Ye Y, Martinez JD, Huang MH, Lui CY, Perez-Polo JR, Uretsky BF. Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin. Am J Physiol Heart Circ Physiol. 2007;292:H2891–7.

    Article  CAS  PubMed  Google Scholar 

  9. Birnbaum Y, Nanhwan MK, Ling S, Perez-Polo JR, Ye Y, Bajaj M. PTEN upregulation may explain the development of insulin resistance and type 2 diabetes with high dose statins. Cardiovasc Drugs Ther. 2014;28:447–57.

    Article  CAS  PubMed  Google Scholar 

  10. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Huang MH, Perez-Polo JR, Uretsky BF. Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart. Prostaglandins Other Lipid Mediat. 2007;83:89–98.

    Article  CAS  PubMed  Google Scholar 

  11. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, Huang MH, Uretsky BF, Perez-Polo JR. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006;114:929–35.

    Article  CAS  PubMed  Google Scholar 

  12. Birnbaum Y, Ye Y, Rosanio S, Tavackoli S, Hu ZY, Schwarz ER, Uretsky BF. Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res. 2005;65:345–55.

    Article  CAS  PubMed  Google Scholar 

  13. Bonello L, Laine M, Kipson N, Mancini J, Helal O, Fromonot J, Gariboldi V, Condo J, Thuny F, Frere C, Camoin-Jau L, Paganelli F, Dignat-George F, Guieu R. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2014;63:872–7.

    Article  CAS  PubMed  Google Scholar 

  14. Bulhak A, Roy J, Hedin U, Sjoquist PO, Pernow J. Cardioprotective effect of rosuvastatin in vivo is dependent on inhibition of geranylgeranyl pyrophosphate and altered RhoA membrane translocation. Am J Physiol Heart Circ Physiol. 2007;292:H3158–63.

    Article  CAS  PubMed  Google Scholar 

  15. Cai W, Fang J, Chen ZY, Lin YL, Wu LM, Chen LL. Rosuvastatin enhances the protective effects of ischemic postconditioning on myocardial ischaemia-reperfusion injury in type 2 diabetic rat. Zhonghua Xin Xue Guan Bing Za Zhi. 2010;38:814–8.

    CAS  PubMed  Google Scholar 

  16. Cattaneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol. 2014;63:2503–9.

    Article  CAS  PubMed  Google Scholar 

  17. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med. 2015;21:1071–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Davaro F, Forde SD, Garfield M, Jiang Z, Halmen K, Tamburro ND, Kurt-Jones E, Fitzgerald KA, Golenbock DT, Wang D. 3-hydroxyl-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1beta interferes with mature IL-1beta signaling. J Biol Chem. 2014;289:16214–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dinicolantonio JJ, Serebruany VL. Exploring the ticagrelor-statin interplay in the PLATO trial. Cardiology. 2013;124:105–7.

    Article  CAS  PubMed  Google Scholar 

  20. Fan Y, Yang S, Zhang X, Cao Y, Huang Y. Comparison of cardioprotective efficacy resulting from a combination of atorvastatin and ischaemic post-conditioning in diabetic and non-diabetic rats. Clin Exp Pharmacol Physiol. 2012;39:938–43.

    Article  CAS  PubMed  Google Scholar 

  21. Henriksbo BD, Lau TC, Cavallari JF, Denou E, Chi W, Lally JS, Crane JD, Duggan BM, Foley KP, Fullerton MD, Tarnopolsky MA, Steinberg GR, Schertzer JD. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes. 2014;63:3742–7.

    Article  CAS  PubMed  Google Scholar 

  22. Henriksbo BD, Schertzer JD. Is immunity a mechanism contributing to statin-induced diabetes? Adipocyte. 2015;4:232–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123:594–604.

    Article  CAS  PubMed  Google Scholar 

  24. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O’Gara PT, Sabatine MS, Smith PK, Smith SC, Jr. (2016) 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation

  25. Liao YH, Lin YC, Tsao ST, Lin YC, Yang AJ, Huang CT, Huang KC, Lin WW. HMG-CoA reductase inhibitors activate caspase-1 in human monocytes depending on ATP release and P2X7 activation. J Leukoc Biol. 2013;93:289–99.

    Article  CAS  PubMed  Google Scholar 

  26. Luo B, Li B, Wang W, Liu X, Liu X, Xia Y, Zhang C, Zhang Y, Zhang M, An F. Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model. Cardiovasc Drugs Ther. 2014;28:33–43.

    Article  CAS  PubMed  Google Scholar 

  27. Manickavasagam S, Ye Y, Lin Y, Perez-Polo RJ, Huang MH, Lui CY, Hughes MG, McAdoo DJ, Uretsky BF, Birnbaum Y. The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation. Cardiovasc Drugs Ther. 2007;21:321–30.

    Article  CAS  PubMed  Google Scholar 

  28. Merla R, Ye Y, Lin Y, Manickavasagam S, Huang MH, Perez-Polo RJ, Uretsky BF, Birnbaum Y. The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation. Am J Physiol Heart Circ Physiol. 2007;293:H1918–28.

    Article  CAS  PubMed  Google Scholar 

  29. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan HR, Menna AC, Voelkel NF, Abbate A. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A. 2011;108:19725–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mitchell P, Marette A. Statin-induced insulin resistance through inflammasome activation: sailing between Scylla and Charybdis. Diabetes. 2014;63:3569–71.

    Article  CAS  PubMed  Google Scholar 

  31. Montero MT, Matilla J, Gomez-Mampaso E, Lasuncion MA. Geranylgeraniol regulates negatively caspase-1 autoprocessing: implication in the Th1 response against mycobacterium tuberculosis. J Immunol. 2004;173:4936–44.

    Article  CAS  PubMed  Google Scholar 

  32. Nanhwan MK, Ling S, Kodakandla M, Nylander S, Ye Y, Birnbaum Y. Chronic treatment with ticagrelor limits myocardial infarct size: an adenosine and cyclooxygenase-2-dependent effect. Arterioscler Thromb Vasc Biol. 2014;34:2078–85.

    Article  CAS  PubMed  Google Scholar 

  33. Nylander S, Femia EA, Scavone M, Berntsson P, Asztely AK, Nelander K, Lofgren L, Nilsson RG, Cattaneo M (2013) Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y antagonism. J Thromb Haemost

  34. O’Gara PT, Kushner FG, Ascheim DD, Casey Jr DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;61:e78–140.

    Article  PubMed  Google Scholar 

  35. Sanada S, Asanuma H, Minamino T, Node K, Takashima S, Okuda H, Shinozaki Y, Ogai A, Fujita M, Hirata A, Kim J, Asano Y, Mori H, Tomoike H, Kitamura S, Hori M, Kitakaze M. Optimal windows of statin use for immediate infarct limitation: 5′-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase. Circulation. 2004;110:2143–9.

    Article  CAS  PubMed  Google Scholar 

  36. Sandanger O, Gao E, Ranheim T, Bliksoen M, Kaasboll OJ, Alfsnes K, Nymo SH, Rashidi A, Ohm IK, Attramadal H, Aukrust P, Vinge LE, Yndestad A. NLRP3 inflammasome activation during myocardial ischemia reperfusion is cardioprotective. Biochem Biophys Res Commun. 2016;469:1012–20.

    Article  CAS  PubMed  Google Scholar 

  37. Sandanger O, Ranheim T, Vinge LE, Bliksoen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 2013;99:164–74.

    Article  CAS  PubMed  Google Scholar 

  38. Satoh M, Tabuchi T, Itoh T, Nakamura M. NLRP3 inflammasome activation in coronary artery disease: results from prospective and randomized study of treatment with atorvastatin or rosuvastatin. Clin Sci (Lond). 2014;126:233–41.

    Article  CAS  Google Scholar 

  39. Sillen H, Cook M, Davis P. Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:2299–306.

    Article  CAS  PubMed  Google Scholar 

  40. Thomas MR, Outteridge SN, Ajjan RA, Phoenix F, Sangha GK, Faulkner RE, Ecob R, Judge HM, Khan H, West LE, Dockrell DH, Sabroe I, Storey RF. Platelet P2Y12 inhibitors reduce systemic inflammation and its Prothrombotic effects in an experimental human model. Arterioscler Thromb Vasc Biol. 2015;35:2562–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thurnher M, Nussbaumer O, Gruenbacher G. Novel aspects of mevalonate pathway inhibitors as antitumor agents. Clin Cancer Res. 2012;18:3524–31.

    Article  CAS  PubMed  Google Scholar 

  42. Toldo S, Marchetti C, Mauro AG, Chojnacki J, Mezzaroma E, Carbone S, Zhang S, Van Tassell B, Salloum FN, Abbate A. Inhibition of the NLRP3 inflammasome limits the inflammatory injury following myocardial ischemia-reperfusion in the mouse. Int J Cardiol. 2016;209:215–20.

    Article  PubMed  Google Scholar 

  43. Toldo S, Mezzaroma E, Van Tassell BW, Farkas D, Marchetti C, Voelkel NF, Abbate A. Interleukin-1beta blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse. Exp Physiol. 2013;98:734–45.

    Article  CAS  PubMed  Google Scholar 

  44. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.

    Article  CAS  PubMed  Google Scholar 

  45. Wojcik WJ, Neff NH. Adenosine measurement by a rapid HPLC-fluorometric method: induced changes of adenosine content in regions of rat brain. J Neurochem. 1982;39:280–2.

    Article  CAS  PubMed  Google Scholar 

  46. Xu JF, Washko GR, Nakahira K, Hatabu H, Patel AS, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, Ross JC, Estepar RS, Diaz AA, Li HP, Qu JM, Himes BE, Come CE, D’Aco K, Martinez FJ, Han MK, Lynch DA, Crapo JD, Morse D, Ryter SW, Silverman EK, Rosas IO, Choi AM, Hunninghake GM, Investigators CO. Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med. 2012;185:547–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang Y, Mou Y, Hu SJ, Fu M. Beneficial effect of rosuvastatin on cardiac dysfunction is associated with alterations in calcium-regulatory proteins. Eur J Heart Fail. 2009;11:6–13.

    Article  CAS  PubMed  Google Scholar 

  48. Ye Y, Abu Said GH, Lin Y, Manickavasagam S, Hughes MG, McAdoo DJ, Perez-Polo RJ, Birnbaum Y. Caffeinated coffee blunts the myocardial protective effects of statins against ischemia-reperfusion injury in the rat. Cardiovasc Drugs Ther. 2008;22:275–82.

    Article  CAS  PubMed  Google Scholar 

  49. Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol. 2015;35:1805–14.

    Article  CAS  PubMed  Google Scholar 

  50. Ye Y, Lin Y, Perez-Polo JR, Uretsky BF, Ye Z, Tieu BC, Birnbaum Y. Phosphorylation of 5-lipoxygenase at ser523 by protein kinase a determines whether pioglitazone and atorvastatin induce proinflammatory leukotriene B4 or anti-inflammatory 15-epi-lipoxin a4 production. J Immunol. 2008;181:3515–23.

    Article  CAS  PubMed  Google Scholar 

  51. Ye Y, Lin Y, Perez-Polo R, Huang MH, Hughes MG, McAdoo DJ, Manickavasagam S, Uretsky BF, Birnbaum Y. Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination. Am J Physiol Heart Circ Physiol. 2007;293:H813–8.

    Article  CAS  PubMed  Google Scholar 

  52. Ye Y, Long B, Qian J, Perez-Polo JR, Birnbaum Y. Dipyridamole with low-dose aspirin augments the infarct size-limiting effects of simvastatin. Cardiovasc Drugs Ther. 2010;24:391–9.

    Article  CAS  PubMed  Google Scholar 

  53. Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol. 2008;295:H343–51.

    Article  CAS  PubMed  Google Scholar 

  54. Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y. The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2011;106:925–52.

    Article  CAS  PubMed  Google Scholar 

  55. Ye Y, Perez-Polo JR, Birnbaum Y. Protecting against ischemia-reperfusion injury: antiplatelet drugs, statins, and their potential interactions. Ann N Y Acad Sci. 2010;1207:76–82.

    Article  CAS  PubMed  Google Scholar 

  56. Zaitone SA, Abo-Gresha NM. Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF. Eur J Pharmacol. 2012;691:134–42.

    Article  CAS  PubMed  Google Scholar 

  57. Zhou X, Rougee LR, Bedwell DW, Cramer JW, Mohutsky MA, Calvert NA, Moulton RD, Cassidy KC, Yumibe NP, Adams LA, Ruterbories KJ. Difference in the pharmacokinetics and hepatic metabolism of Antidiabetic drugs in Zucker diabetic fatty and Sprague-Dawley rats. Drug Metab Dispos. 2016;44:1184–92.

    Article  CAS  PubMed  Google Scholar 

  58. Zuurbier CJ, Jong WM, Eerbeek O, Koeman A, Pulskens WP, Butter LM, Leemans JC, Hollmann MW. Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling. PLoS One. 2012;7:e40643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The study was by an investigator initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yumei Ye.

Ethics declarations

Funding

This study was funded by an investigator initiated grant from AstraZeneca and the John S. Dunn Chair in Cardiology Research and Education.

Disclosure of Potential Conflict of Interest

Dr. Nylander is an employee of Astra Zeneca.

Dr. Ye receives research grants from Astra Zeneca and Boehringer Ingelheim.

Dr. Yochai Birnbaum receives research grants from Astra Zeneca and he is a speaker for AstraZeneca.

Dr. G.D. Birnbaum and Dr. I. Birnbaum report no conflicts.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The study was approved by the UTMB IACUC.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Birnbaum, Y., Birnbaum, G.D., Birnbaum, I. et al. Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine. Cardiovasc Drugs Ther 30, 539–550 (2016). https://doi.org/10.1007/s10557-016-6701-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-016-6701-2

Keywords

Navigation