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The Cardioprotective Effect of a Statin and Cilostazol Combination: Relationship to Akt and Endothelial Nitric Oxide Synthase Activation

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Abstract

Background

Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. Hypothesis: CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction.

Methods

Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl–tetrazolium–chloride.

Results

Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 ± 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 ± 7%).

Conclusions

ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.

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Acknowledgements

This study is supported by a grant from the Edward D. and Sally M. Futch Endowment of the Division of Cardiology, UTMB.

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Authors and Affiliations

  1. The Division of Cardiology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Blvd., Galveston, TX, 77555-0553, USA

    Saraswathy Manickavasagam, Yumei Ye, Yu Lin, Ming-He Huang, Charles Y. Lui, Barry F. Uretsky & Yochai Birnbaum

  2. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Blvd., Galveston, TX, 77555-0553, USA

    Yumei Ye, Regino J. Perez-Polo & Yochai Birnbaum

  3. The Department of Neuroscience & Cell Biology, University of Texas Medical Branch, 5.106 John Sealy Annex, 301 University Blvd., Galveston, TX, 77555-0553, USA

    Michael G. Hughes & David J. McAdoo

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  1. Saraswathy Manickavasagam
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Manickavasagam, S., Ye, Y., Lin, Y. et al. The Cardioprotective Effect of a Statin and Cilostazol Combination: Relationship to Akt and Endothelial Nitric Oxide Synthase Activation. Cardiovasc Drugs Ther 21, 321–330 (2007). https://doi.org/10.1007/s10557-007-6036-0

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