Leptin upregulates the expression of plasminogen activator inhibitor-1 in human vascular endothelial cells

Prachi Singh, Timothy E. Peterson, Kara R. Barber, Fatima Sert Kuniyoshi, Andrus Jensen, Michal Hoffmann, Abu S.M. Shamsuzzaman, Virend K. Somers

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

A prothrombotic state in obesity may be partially responsible for the higher incidence of atherosclerotic complications. However the factors responsible for this prothrombotic state, linked with high levels of plasminogen activator inhibitor-1 (PAI-1), are not fully known. Leptin is elevated in obesity and studies have shown a positive correlation between leptin and PAI-1 levels in human subjects, along with a negative correlation with tissue-type plasminogen activator (tPA). We tested the hypothesis that leptin induces PAI-1 and inhibits tPA expression using human coronary artery endothelial cells (HCAEC) in culture as these cells play an important role in atherosclerosis. We demonstrate that leptin induces the transcription and translation of PAI-1 in HCAEC. The leptin dependent upregulation of PAI-1 mRNA and protein was comparable to insulin-induced PAI-1 expression. We show leptin concentration (0-150 ng/ml) dependent increases in PAI-1 mRNA and protein after 6 and 12 h of leptin administration, respectively. Increased intracellular PAI-1 expression correlates with increased PAI-1 activity in conditioned media and inhibition of specific ERK1/2 pathway by treatment with PD98059 (20-40 μM) inhibits leptin dependent PAI-1 expression. However no changes in tPA expression were seen with time or increasing concentrations of leptin. Also leptin treatment did not alter total tPA concentration or tPA activity in conditioned media. In conclusion, our study shows that leptin upregulates the expression of PAI-1 in vascular endothelial cells via activation of ERK1/2 but does not regulate tPA expression. These studies demonstrate a novel mechanism for the prothrombotic role of leptin in development of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)47-52
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume392
Issue number1
DOIs
StatePublished - Jan 29 2010

Keywords

  • Atherosclerosis
  • Fibrinolysis
  • Leptin
  • Obesity
  • Plasminogen activator inhibitor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Leptin upregulates the expression of plasminogen activator inhibitor-1 in human vascular endothelial cells'. Together they form a unique fingerprint.

Cite this