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MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced

Maria Luisa Guarino1, Isabella Massimi1, Laura Alemanno1

  • 1Department of Experimental Medicine, "Sapienza" - University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.

Journal of Thrombosis and Thrombolysis
|August 18, 2020
PubMed

Insights

Inhibition of multidrug resistance protein 4 (MRP4) by cilostazol reduces platelet aggregation in patients with high on aspirin residual platelet reactivity (HARPR), improving nitric oxide (NO) effects.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Hematology

Background:

  • Multidrug resistance protein 4 (MRP4) role in platelet function and nitric oxide (NO) resistance is not fully understood.
  • Platelet hyper-reactivity in patients with high on aspirin residual platelet reactivity (HARPR) poses a clinical challenge.
  • Cilostazol is known to inhibit MRP4, but its specific effects on platelet NO resistance and aggregation require further investigation.

Purpose of the Study:

  • To determine if platelet nitric oxide (NO) resistance correlates with MRP4 expression.
  • To evaluate the efficacy of in vitro MRP4 inhibition by cilostazol in reducing platelet NO resistance.
  • To assess the impact of MRP4 inhibition on adenosine diphosphate (ADP)-induced platelet aggregation, particularly in HARPR patients.

Main Methods:

  • Assessed the inhibitory effect of sodium nitroprusside (SNP), a NO-donor, on ADP-induced platelet aggregation in platelets from aspirin-treated patients and controls.
  • Investigated the impact of MRP4 on ADP-induced platelet aggregation in HARPR patients, healthy volunteers (HV), and a control cohort (CTR).
  • Administered cilostazol to inhibit MRP4 in vitro and measured its effects on platelet aggregation.

Main Results:

  • Aspirin-treated patients with high MRP4 levels exhibited reduced SNP inhibition compared to those with low MRP4 levels.
  • Cilostazol-mediated MRP4 inhibition significantly reduced ADP-induced platelet aggregation in HARPR patients.
  • MRP4 inhibition by cilostazol also reduced platelet aggregation in healthy volunteers (HV) and control cohorts (CTR), though to a lesser extent.

Conclusions:

  • Platelet NO resistance is associated with MRP4 expression levels.
  • Cilostazol effectively mitigates the hyper-reactive platelet phenotype in HARPR patients by inhibiting MRP4.
  • Cilostazol enhances NO-dependent antiplatelet effects, reducing residual ADP-induced platelet aggregation.
Keywords:
AspirinCilostazolMultidrug resistance protein 4Nitric oxidePlatelet aggregation

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