Nifedipine indirectly upregulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways

Keisuke Fukuo, Jin Yang, Osamu Yasuda, Masaki Mogi, Toshimitsu Suhara, Naoyuki Sato, Takashi Suzuki, Shigeto Morimoto, Toshio Ogihara

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Background - Calcium antagonists normalize endothelial dysfunction in many cardiovascular diseases. There is no known receptor, however, for calcium antagonists in endothelial cells (ECs). We hypothesized that vascular smooth muscle cells (VSMCs) are involved in the mechanism underlying the normalization of endothelial dysfunction by calcium antagonists. Methods and Results - Coculture studies with ECs and VSMCs were performed to determine whether VSMCs mediate modulation of endothelial superoxide dismutase (SOD) activity and expression induced by the calcium antagonist nifedipine. Nifedipine induced upregulation of SOD activity in rat aortic segments but had no effect on SOD expression or activity in ECs or VSMCs cultured individually. When ECs were cocultured with VSMCs, however, nifedipine upregulated SOD expression and activity in ECs. Nifedipine stimulated vascular endothelial growth factor (VEGF) production from VSMCs, and this stimulation of VEGF production was abolished by HOE-140, an antagonist of the bradykinin B2 receptor. A neutralizing antibody against VEGF inhibited the upregulation of endothelial SOD by nifedipine. In addition, recombinant VEGF induced an increase in the levels of SOD expression in ECs, and supernatant derived from nifedipine-treated VSMCs enhanced NO production from ECs. This increase in NO production by the supernatant was inhibited by preincubation of ECs with SOD antisense oligodeoxyribonucleotides. Conclusions - The calcium antagonist nifedipine indirectly upregulates endothelial SOD expression by stimulating VEGF production from adjacent VSMCs. This finding may provide further insight into the mechanism underlying the beneficial effects of calcium antagonists in cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)356-361
Number of pages6
JournalCirculation
Volume106
Issue number3
DOIs
StatePublished - Jul 16 2002
Externally publishedYes

Keywords

  • Bradykinin
  • Calcium
  • Endothelium
  • Muscle, Smooth
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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