Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine.
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.


OBJECTIVE
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.
The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA.|The section of Cardiology, Baylor College of Medicine, Houston, TX, 77030, USA.
Yochai
http://orcid.org/0000-0001-7653-6328
Y
Birnbaum
The Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Gilad D
GD
Birnbaum
The section of Cardiology, Baylor College of Medicine, Houston, TX, 77030, USA.
Itamar
I
Birnbaum
AstraZeneca R&D, Mölndal, Sweden.
Sven
S
Nylander
The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA. yumye@utmb.edu.
Yumei
Y
Ye
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D004357:Drug Synergism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000068799:Prasugrel Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011924:Rats, Zucker; D000068718:Rosuvastatin Calcium / Q000494:pharmacology / Q000627:therapeutic use*; D000077486:Ticagrelor
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D044045:Lipoxins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; C498535:Pycard protein, rat; D012333:RNA, Messenger; C040527:lipoxin A4; D000068718:Rosuvastatin Calcium; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068799:Prasugrel Hydrochloride; D000077486:Ticagrelor; D000241:Adenosine
Adenosine; Diabetes mellitus; Infarct size; Ischemia-reperfusion; Statin; Ticagrelor