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Ischemia/reperfusion-induced MKP-3 impairs endothelial NO formation via inactivation of ERK1/2 pathway

Dan Yang1, Ping Xie, Zhihua Liu

  • 1Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Plos One
|August 1, 2012
PubMed

Insights

Ischemia/reperfusion injury impairs endothelial Nitric oxide (NO) production via Mitogen-activated protein kinase phosphatase-3 (MKP-3) by inactivating ERK1/2 and recruiting HDAC1. Salvianolic acid A protects against this NO deficiency.

Area of Science:

  • Endothelial biology
  • Molecular mechanisms of cell signaling
  • Cardiovascular research

Background:

  • Mitogen-activated protein kinase phosphatases (MKPs), including MKP-3, are expressed in endothelial cells, but their specific roles in endothelial function remain unclear.
  • Nitric oxide (NO) production is critical for endothelial health, and its dysregulation is implicated in various vascular pathologies.

Purpose of the Study:

  • To investigate the role of MKP-3 in endothelial Nitric oxide (NO) formation under ischemia/reperfusion (IS/RP) conditions.
  • To elucidate the molecular mechanisms underlying MKP-3-mediated effects on endothelial NO production.
  • To evaluate the therapeutic potential of Salvianolic acid A (SalA) in mitigating IS/RP-induced endothelial dysfunction.

Main Methods:

  • Human umbilical vein endothelial cells (HUVECs) were subjected to IS/RP treatment.
  • MKP-3 expression, eNOS expression, NO formation, and endothelial apoptosis were assessed.
  • siRNA was used to knockdown MKP-3, and constitutively active ERK plasmids were employed.
  • Histone deacetylase (HDAC) inhibitor treatment and HDAC1 recruitment to the eNOS promoter were analyzed.
  • The effect of Salvianolic acid A (SalA) on MKP-3 induction and NO formation was evaluated.

Main Results:

  • IS/RP induced MKP-3 expression, inhibited eNOS expression and NO formation, and increased endothelial apoptosis.
  • MKP-3 knockdown partially restored eNOS expression and NO production.
  • MKP-3 mediated its effects via inactivation of the ERK1/2 pathway.
  • Impairment of eNOS expression was linked to histone deacetylation and HDAC1 recruitment to the eNOS promoter.
  • SalA treatment significantly attenuated IS/RP-induced MKP-3 upregulation and NO formation inhibition.

Conclusions:

  • MKP-3 plays a crucial role in IS/RP-induced inhibition of endothelial NO formation.
  • The mechanism involves MKP-3-dependent inactivation of ERK1/2 and recruitment of HDAC1 to the eNOS promoter.
  • Salvianolic acid A demonstrates therapeutic potential in protecting endothelial cells from IS/RP-induced NO deficiency.

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