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Bimodal Effects of P2Y12 Antagonism on Matrix Metalloproteinase–Associated Contractile Dysfunction in İnsulin-Resistant Mammalian Heart

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Abstract

The matrix metalloproteinases (MMPs) contribute to matrix remodeling in diabetes via tissue degradation; however, their contributions can be different depending on the pathology. For instance, MMPs are elevated in acute stress hyperglycemia, whereas they can be degraded in chronic hyperglycemia. Since studies emphasize the possible cardioprotective effect of ticagrelor (Tica) beyond its antiplatelet action, we aimed to examine whether Tica treatment can reverse the depressed heart function of metabolic syndrome (MetS) rats via affecting the expression levels of MMPs. Tica treatment of high-carbohydrate-induced MetS rats could not affect significantly the depressed contractile activity of Langendorff-perfused heart preparations. On the other hand, the Tica treatment provided a significant recovery in the reduced relaxation activity of the aortic preparations from the same animals. Histological examination of the hearts demonstrated marked damages in Mets rats, such as increases in the number of foamy cells and accumulation of collagen fiber and increases in the elastic lamellar irregularity of tunica media, while Tica treatment provided a slight improvement in the structure of left ventricle tissue. We also could not obtain a significant reverse in the high cytosolic labile Zn2+ ([Zn2+]i) with the treatment of cardiomyocytes with Tica. Furthermore, Tica treatment of MetS rats could not significantly reverse the degraded protein levels of MMP-2 and MMP-9 in the heart, as well. Overall, we demonstrated that Tica treatment of MetS rats has no significant benefits on the depressed heart function, although provide a significant beneficial impact on vascular relaxation. This action of Tica may be through its lack of action on both MMP degradation and high [Zn2+]i, which can further precipitate in cleavage of extracellular matrix in the heart.

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Funding

This work was supported by grants (No. SGAB-216S979) from The Scientific and Technological Research Council of Turkey.

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Authors and Affiliations

  1. Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey

    Yusuf Olgar, Erkan Tuncay & Belma Turan

  2. Department of Histology and Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey

    Deniz Billur

  3. Department of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey

    Belma Turan

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  1. Yusuf Olgar
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  2. Erkan Tuncay
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  3. Deniz Billur
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  4. Belma Turan
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Contributions

BT designed and supervised the research and provided the final approval of the version to be published; YO and ET contributed and performed the experiments and analyzed the data; DB performed all light and electron microscopic analysis. All authors discussed the results and commented on the manuscript.

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Correspondence to Belma Turan.

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All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Ankara University. All animals received humane care under an institutionally approved experimental animal protocol with an ethical license in Turkey.

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Olgar, Y., Tuncay, E., Billur, D. et al. Bimodal Effects of P2Y12 Antagonism on Matrix Metalloproteinase–Associated Contractile Dysfunction in İnsulin-Resistant Mammalian Heart. Biol Trace Elem Res 200, 2195–2204 (2022). https://doi.org/10.1007/s12011-021-02816-w

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