The cardioprotective effect of a statin and cilostazol combination

Relationship to Akt and endothelial nitric oxide synthase activation

Saraswathy Manickavasagam, Yumei Ye, Yu Lin, Regino J. Perez-Polo, Ming He Huang, Charles Y. Lui, Michael G. Hughes, David J. McAdoo, Barry F. Uretsky, Yochai Birnbaum

Research output: Contribution to journalArticle

61 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalCardiovascular Drugs and Therapy
Volume21
Issue number5
DOIs
StatePublished - Oct 2007

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Nitric Oxide Synthase Type III
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
Reperfusion
cilostazol
Atorvastatin Calcium
Ischemia
Type 3 Cyclic Nucleotide Phosphodiesterases
Phosphodiesterase Inhibitors
Coronary Occlusion
Body Size
Immunoblotting
Sprague Dawley Rats
Chlorides
Coronary Vessels
Coloring Agents
Heart Rate
Myocardial Infarction
Body Weight

Keywords

  • Adenosine
  • Atorvastatin
  • Cilostazol
  • Cyclic AMP
  • Endothelial nitric oxide synthase
  • Infarct size
  • Ischemia-reperfusion injury
  • Protein kinase A

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

The cardioprotective effect of a statin and cilostazol combination : Relationship to Akt and endothelial nitric oxide synthase activation. / Manickavasagam, Saraswathy; Ye, Yumei; Lin, Yu; Perez-Polo, Regino J.; Huang, Ming He; Lui, Charles Y.; Hughes, Michael G.; McAdoo, David J.; Uretsky, Barry F.; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 21, No. 5, 10.2007, p. 321-330.

Research output: Contribution to journalArticle

Manickavasagam, S, Ye, Y, Lin, Y, Perez-Polo, RJ, Huang, MH, Lui, CY, Hughes, MG, McAdoo, DJ, Uretsky, BF & Birnbaum, Y 2007, 'The cardioprotective effect of a statin and cilostazol combination: Relationship to Akt and endothelial nitric oxide synthase activation', Cardiovascular Drugs and Therapy, vol. 21, no. 5, pp. 321-330. https://doi.org/10.1007/s10557-007-6036-0
Manickavasagam, Saraswathy ; Ye, Yumei ; Lin, Yu ; Perez-Polo, Regino J. ; Huang, Ming He ; Lui, Charles Y. ; Hughes, Michael G. ; McAdoo, David J. ; Uretsky, Barry F. ; Birnbaum, Yochai. / The cardioprotective effect of a statin and cilostazol combination : Relationship to Akt and endothelial nitric oxide synthase activation. In: Cardiovascular Drugs and Therapy. 2007 ; Vol. 21, No. 5. pp. 321-330.
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T1 - The cardioprotective effect of a statin and cilostazol combination

T2 - Relationship to Akt and endothelial nitric oxide synthase activation

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AU - Lin, Yu

AU - Perez-Polo, Regino J.

AU - Huang, Ming He

AU - Lui, Charles Y.

AU - Hughes, Michael G.

AU - McAdoo, David J.

AU - Uretsky, Barry F.

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N2 - 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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