The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells

Nina Grosser, Anke Hemmerle, Georg Berndt, Kati Erdmann, Urte Hinkelmann, Stephan Schürgerc, Nastiti Wijayanti, Stephan Immenschuh, Henning Schröder

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Cholesterol-independent, pleiotropic actions of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert anti-inflammatory and antioxidant action by as yet unidentified mechanisms. This study explores the role of heme oxygenase 1 (HO-1) as a target and mediator of statins. In cultured endothelial cells derived from human umbilical vein, simvastatin and lovastatin increased HO-1 mRNA levels in a concentration- and time-dependent fashion. HO-1 induction by statins remained unaffected by mevalonate and N-nitro-l-arginine methyl ester, precluding the involvement of isoprenoid- and NO-dependent pathways. HO-1 mRNA induction was abrogated in the presence of actinomycin D and cycloheximide. In cells transfected with a reporter gene construct containing the proximal 4 kB of the HO-1 gene promoter 5′-flanking region, significant upregulation of promoter activity was detected, indicating that regulatory elements binding to this region were involved in transcriptional HO-1 induction by statins. Increased transcriptional expression of HO-1 was associated with elevated HO-1 protein levels and reduction of free radical formation. Our results show that the antioxidant defense protein HO-1 is a target site of statins in endothelial cells. Statins lead to HO-1 promoter activation, transcript and protein accumulation. This novel pathway may contribute to and explain the pleiotropic antioxidant, anti-inflammatory, and antiatherogenic actions of statins.

Original languageEnglish (US)
Pages (from-to)2064-2071
Number of pages8
JournalFree Radical Biology and Medicine
Volume37
Issue number12
DOIs
StatePublished - Dec 15 2004

Bibliographical note

Funding Information:
This work was supported by the German Federal Department of Education and Research (BMBF Collaborative Program Grant "Nutrition and Atherosclerosis," No. 0312750A).

Keywords

  • Antioxidant
  • Endothelial cells
  • Free radicals
  • Heme oxygenase
  • Hydroxymethylglutaryl coenzyme A reductase inhibitor

Fingerprint

Dive into the research topics of 'The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells'. Together they form a unique fingerprint.

Cite this