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Bis (Aspirinato) Zinc (II) Complex Successfully Inhibits Carotid Arterial Neointima Formation after Balloon-injury in Rats

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Abstract

Purpose

Neointima formation following angioplasty is a serious consequence of endothelial damage in arteries. Inflammatory mediators and lack of endothelial regulatory mechanisms lead to migration and proliferation of smooth-muscle cells and thus to restenosis. This study examines the effect of the novel bis (aspirinato) zinc (II) complex on neointima formation in a rat model of carotid balloon-injury.

Methods

Rats underwent balloon-injury of the right common carotid artery, then received PEG400 vehicle (untreated-group), acetylsalicylic-acid (ASA-group), zinc-chloride (Zn-group) and bis (aspirinato) zinc (II) complex (Zn(ASA) 2-group) orally for 18 consecutive days. From harvested carotid arteries, histology, immunohistochemistry and mRNA expression analysis were performed.

Results

Compared to the untreated-group, Zn (ASA) 2-treatment significantly lowered stenosis ratio (54.0 ± 5.8 % to 25.5 ± 3.9 %) and reduced neointima/media ratio (1.5 ± 0.2 to 0.5 ± 0.1). Significantly higher alpha smooth muscle actin mRNA and protein expression were measured after Zn (ASA)2 and Zn-treatment in comparison with the untreated and ASA-groups while the expression of matrix-metalloproteinase-9 was significantly higher in these groups compared to Zn (ASA)2. The presence of collagen in media was significantly decreased in all treated groups. mRNA expressions of nuclear factor kappa-b, transforming growth-factor-β and proliferating cell nuclear antigen were significantly down-regulated, whereas a20 was up-regulated by Zn (ASA)2 treatment compared to the untreated and ASA-groups.

Conclusion

This study proves the effectivity of the novel bis (aspirinato) zinc complex in reducing neointima formation and restenosis after balloon-injury and supports the hypothesis that inhibition of smooth-muscle transformation/proliferation plays a key role in the prevention of restenosis.

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Acknowledgments

The expert technical assistance of Patricia Kraft, Tobias Mayer and Samel Alsaid is gratefully acknowledged.

Funding

This study was supported by the Land Baden-Württemberg, Germany, by the Medical Faculty of the University of Heidelberg, Germany (to S. Korkmaz), by the School of PhD Studies, Semmelweis University, Hungary (to P. Hegedűs), and by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (to T. Radovits).

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Authors and Affiliations

  1. Department of Cardiac Surgery, University of Heidelberg, INF 326, Heidelberg, 69120, Germany

    Péter Hegedűs, Sevil Korkmaz, Harald Schmidt, Shiliang Li, Matthias Karck & Gábor Szabó

  2. Heart and Vascular Center, Semmelweis University, Budapest, Hungary

    Péter Hegedűs, Tamás Radovits & Béla Merkely

  3. Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan

    Yutaka Yoshikawa & Hiroyuki Yasui

Authors
  1. Péter Hegedűs
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  2. Sevil Korkmaz
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  3. Tamás Radovits
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  4. Harald Schmidt
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  5. Shiliang Li
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  6. Yutaka Yoshikawa
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  7. Hiroyuki Yasui
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  8. Béla Merkely
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  9. Matthias Karck
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  10. Gábor Szabó
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Corresponding author

Correspondence to Péter Hegedűs.

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Hegedűs, P., Korkmaz, S., Radovits, T. et al. Bis (Aspirinato) Zinc (II) Complex Successfully Inhibits Carotid Arterial Neointima Formation after Balloon-injury in Rats. Cardiovasc Drugs Ther 28, 533–539 (2014). https://doi.org/10.1007/s10557-014-6549-2

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  • DOI: https://doi.org/10.1007/s10557-014-6549-2

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