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Ticagrelor and Rosuvastatin Have Additive Cardioprotective Effects via Adenosine

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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.

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Acknowledgments

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

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Authors and Affiliations

  1. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555, USA

    Yochai Birnbaum & Yumei Ye

  2. The section of Cardiology, Baylor College of Medicine, Houston, TX, 77030, USA

    Yochai Birnbaum & Itamar Birnbaum

  3. The Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    Gilad D. Birnbaum

  4. AstraZeneca R&D, Mölndal, Sweden

    Sven Nylander

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  1. Yochai Birnbaum
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Correspondence to Yumei Ye.

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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.

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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

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