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PAF enhances MMP-2 production in rat aortic VSMCs via a β-arrestin2-dependent ERK signaling pathway

Yun H Kim1, Seung J Lee, Kyo W Seo

  • 1Departments of Pharmacology and Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea.

Journal of Lipid Research
|August 6, 2013
PubMed

Insights

Platelet-activating factor (PAF) boosts matrix metalloproteinase-2 (MMP-2) in vascular cells. This occurs through a signaling pathway involving ERK and β-arrestin2, impacting atherosclerosis development.

Area of Science:

  • Cardiovascular Biology
  • Cell Signaling
  • Molecular Medicine

Background:

  • Platelet-activating factor (PAF) is a mediator found in atherosclerotic plaques, but its specific role in disease progression is not fully understood.
  • Matrix metalloproteinases (MMPs) are implicated in the breakdown of extracellular matrix, contributing to atherosclerotic plaque instability.

Purpose of the Study:

  • To investigate the role of Platelet-activating factor (PAF) in regulating matrix metalloproteinase (MMP) production in primary vascular smooth muscle cells (VSMCs).
  • To elucidate the specific signaling pathways, including ERK and β-arrestin2, involved in PAF-mediated MMP production.

Main Methods:

  • Primary rat aortic VSMCs were stimulated with PAF.
  • Expression levels of MMP-2 and MMP-9 mRNA and protein were analyzed.
  • Inhibition of extracellular signal-regulated kinases (ERKs), p38 MAPK, and JNK pathways was performed using molecular and pharmacological inhibitors.
  • ERK phosphorylation was assessed, and PAF receptor (PAFR) specificity was confirmed.
  • Immunofluorescence and coimmunoprecipitation were used to study the interaction of β-arrestin2, PAFR, and phosphorylated ERK (P-ERK).
  • β-arrestin2 depletion was employed to assess its role in PAF signaling.

Main Results:

  • PAF stimulation significantly increased MMP-2 mRNA and protein expression in VSMCs, but not MMP-9.
  • These increases were attenuated by inhibiting ERK signaling, but not p38 or JNK.
  • PAF induced ERK phosphorylation, which was dependent on the PAF receptor (PAFR) and involved β-arrestin2.
  • β-arrestin2 was found to colocalize and form complexes with PAFR and P-ERK.
  • Depletion of β-arrestin2 significantly reduced PAF-induced ERK phosphorylation and MMP-2 production.

Conclusions:

  • Platelet-activating factor (PAF) enhances MMP-2 production in vascular smooth muscle cells.
  • This effect is mediated through a β-arrestin2-dependent extracellular signal-regulated kinase (ERK) signaling pathway.
  • The findings suggest a novel mechanism by which PAF contributes to atherosclerosis progression via MMP modulation.
Keywords:
extracellular signal-regulated kinasematrix metalloproteinase-2platelet-activating factorplatelet-activating factor receptorβ-arrestin2

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