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

doi:10.1016/j.freeradbiomed.2004.09.009

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

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

152 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 language	English (US)
Pages (from-to)	2064-2071
Number of pages	8
Journal	Free Radical Biology and Medicine
Volume	37
Issue number	12
DOIs	https://doi.org/10.1016/j.freeradbiomed.2004.09.009
State	Published - 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

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

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.",

keywords = "Antioxidant, Endothelial cells, Free radicals, Heme oxygenase, Hydroxymethylglutaryl coenzyme A reductase inhibitor",

author = "Nina Grosser and Anke Hemmerle and Georg Berndt and Kati Erdmann and Urte Hinkelmann and Stephan Sch{\"u}rgerc and Nastiti Wijayanti and Stephan Immenschuh and Henning Schr{\"o}der",

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).",

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doi = "10.1016/j.freeradbiomed.2004.09.009",

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AU - Grosser, Nina

AU - Hemmerle, Anke

AU - Berndt, Georg

AU - Erdmann, Kati

AU - Hinkelmann, Urte

AU - Schürgerc, Stephan

AU - Wijayanti, Nastiti

AU - Immenschuh, Stephan

AU - Schröder, Henning

N1 - Funding Information: This work was supported by the German Federal Department of Education and Research (BMBF Collaborative Program Grant "Nutrition and Atherosclerosis," No. 0312750A).

PY - 2004/12/15

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N2 - 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.

AB - 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.

KW - Antioxidant

KW - Endothelial cells

KW - Free radicals

KW - Heme oxygenase

KW - Hydroxymethylglutaryl coenzyme A reductase inhibitor

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SN - 0891-5849

VL - 37

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EP - 2071

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

IS - 12

ER -

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

Abstract

Bibliographical note

Keywords

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