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Statin‐mediated cytoprotection of human vascular endothelial cells: a role for Kruppel‐like factor 2‐dependent induction of heme oxygenase‐1
Author(s) -
ALI F.,
HAMDULAY S. S.,
KINDERLERER A. R.,
BOYLE J. J.,
LIDINGTON E. A.,
YAMAGUCHI T.,
SOARES M. P.,
HASKARD D. O.,
RANDI A. M.,
MASON J. C.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02787.x
Subject(s) - klf2 , cytoprotection , heme oxygenase , atorvastatin , statin , downregulation and upregulation , chemistry , small interfering rna , pharmacology , hmg coa reductase , umbilical vein , nitric oxide , reductase , medicine , biochemistry , endocrinology , heme , oxidative stress , transfection , enzyme , in vitro , gene
Summary. Background : Heme oxygenase‐1 (HO‐1), by exerting anti‐inflammatory, antiproliferative, antiapoptotic and antioxidant effects in the vasculature, protects against atherosclerosis and post‐transplant vasculopathy. We noted the overlap between the effects of HO‐1 and those attributed to 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors (statins). This led to an investigation of the role of HO‐1 in statin‐mediated cytoprotection in primary human endothelial cells (ECs), and the ability of Kruppel‐like factor 2 (KLF2) to regulate HO‐1 function. Methods/results: Treatment of human umbilical vein and aortic ECs with atorvastatin significantly upregulated HO‐1 promoter activity, mRNA expression and protein expression, increasing HO‐1 enzymatic activity as shown by raised intracellular bilirubin IXα. This effect was indirect, dependent upon inhibition of HMG‐CoA reductase and geranylgeranylation, and independent of nitric oxide or changes in mRNA stability. Atorvastatin protected ECs against the generation of reactive oxygen species and H 2 O 2 ‐induced injury. HO‐1 inhibition, with small interfering RNA (siRNA) or zinc protoporphyrin IX, abrogated atorvastatin‐mediated cytoprotection. Atorvastatin upregulated KLF2 expression, whereas KLF2 siRNA attenuated statin‐induced HO‐1 and its associated antioxidant cytoprotective effects. Iron chelation, adenoviral‐mediated overexpression of ferritin or supplementation of culture media with biliverdin reversed the inhibitory effects of HO‐1 and KLF2 siRNA, suggesting that bile pigments and ferritin mediate the antioxidant actions of statin‐induced HO‐1. Conclusions: We have identified a novel link between KLF2 and HO‐1 in human vascular ECs, demonstrating that atorvastatin‐mediated HO‐1 upregulation, and its associated antioxidant effect, is KLF2‐dependent. The relationship between KLF2 and HO‐1 is likely to represent an important component of the vasculoprotective profile of statins.