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The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via

S P Kastl1, W S Speidl, C Kaun

  • 1Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Journal of Thrombosis and Haemostasis : JTH
|August 2, 2006
PubMed

Insights

Complement component C5a significantly increases plasminogen activator inhibitor-1 (PAI-1) in human macrophages, potentially influencing thrombus formation in atherosclerosis.

Area of Science:

  • Immunology
  • Cardiovascular Biology
  • Molecular Medicine

Background:

  • Atherosclerosis is a chronic inflammatory disease where complement activation plays a key role.
  • Complement components, including C5a, are found in atherosclerotic plaques.
  • Elevated C5a levels correlate with adverse cardiovascular events, suggesting its involvement in disease progression.

Purpose of the Study:

  • To investigate the role of complement components C3a and C5a in regulating plasminogen activator inhibitor-1 (PAI-1) production in human macrophages.
  • To elucidate the signaling pathways involved in C5a-mediated PAI-1 regulation.

Main Methods:

  • Human monocyte-derived macrophages (MDM) and human plaque macrophages were cultured.
  • Macrophages were incubated with complement component C5a.
  • PAI-1 levels were measured using real-time polymerase chain reaction (RT-PCR) and other assays.
  • NF-kappaB activation was assessed using specific inhibitors and DNA binding assays.

Main Results:

  • C5a significantly upregulated PAI-1 expression in both MDM (up to 11-fold) and plaque macrophages (up to 2.7-fold) at both protein and mRNA levels.
  • The C5a-induced PAI-1 increase was mediated through the C5a receptor (C5aR/CD88) and involved NF-kappaB activation.
  • The effects of C5a were independent of TNF-alpha and oxidative burst.

Conclusions:

  • C5a upregulates PAI-1 in macrophages via NF-kappaB activation.
  • This C5a-induced PAI-1 upregulation may promote thrombus development and stabilization within atherosclerotic lesions.
  • Alternatively, C5a-mediated PAI-1 increase in plaque macrophages might serve as a protective mechanism against plaque rupture.
Abstract

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