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Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus

Ken Aizawa1, Youko Takahari2, Naoko Higashijima3

  • 1Product Research Department, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.

Journal of Pharmacological Sciences
|April 4, 2015
PubMed

Insights

Nicorandil (NIC) protects against sirolimus (SRL)-induced thrombosis by reducing reactive oxygen species (ROS) and protecting endothelial cells. This suggests NIC may be a valuable addition for preventing SRL-related blood clot complications.

Area of Science:

  • Cardiovascular Pharmacology
  • Endothelial Biology
  • Thrombosis Research

Background:

  • Sirolimus (SRL) prevents restenosis post-percutaneous coronary intervention but increases thrombosis risk.
  • Reactive oxygen species (ROS) are implicated in endothelial dysfunction and thrombus formation.
  • Endothelial dysfunction and thrombosis are critical complications of SRL therapy.

Purpose of the Study:

  • To investigate the protective effects of nicorandil (NIC) against SRL-induced thrombosis.
  • To elucidate the mechanisms underlying NIC's protective action, focusing on ROS modulation and endothelial protection.
  • To evaluate the therapeutic potential of NIC in preventing SRL-associated thrombosis.

Main Methods:

  • In vitro studies using human coronary artery endothelial cells (HCAECs) to assess ROS production, NADPH oxidase activity, and cell viability.
  • Pharmacological inhibition of specific signaling pathways (5-hydroxydecanoate, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) to identify NIC's targets.
  • In vivo studies using a mouse model of FeCl3-induced thrombosis to evaluate NIC's efficacy in preventing thrombus formation and ROS production.

Main Results:

  • NIC inhibited SRL-induced ROS production in HCAECs, an effect partially dependent on mitochondrial KATP channels.
  • NIC suppressed SRL-induced upregulation of NADPH oxidase p22(phox) mRNA and enhanced superoxide dismutase 2 expression.
  • NIC treatment improved SRL-induced endothelial cell viability and significantly inhibited thrombus formation and ROS production in a mouse thrombosis model.

Conclusions:

  • Nicorandil (NIC) effectively prevents sirolimus (SRL)-induced thrombosis in vitro and in vivo.
  • NIC's protective effects are attributed to the reduction of reactive oxygen species (ROS) and direct endothelial protection.
  • NIC represents a promising therapeutic option to mitigate the thrombotic complications associated with sirolimus therapy.
Keywords:
Endothelial cellsNicorandilReactive oxygen speciesSirolimusThrombosis

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