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Cardiovascular Research Advance Access originally published online on June 12, 2008
Cardiovascular Research 2008 80(1):138-150; doi:10.1093/cvr/cvn160
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

HMG-CoA reductase inhibitors activate the unfolded protein response and induce cytoprotective GRP78 expression

Jui-Ching Chen1, Mei-Lin Wu2, Kuo-Chin Huang3,*,{dagger} and Wan-Wan Lin1,*,{dagger}

1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
3 Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan

* Corresponding authors. Tel: +886 2 23123456, ext. 8315; fax: +886 2 23915297 (Wan-Wan Lin); Tel: +886 2 23123456, ext. 6081; fax: +886 2 23118674 (Kuo-Chin Huang). E-mail addresses: wwl{at}ha.mc.ntu.edu.tw (W.-W. Lin) and chin3{at}ha.mc.ntu.edu.tw (K.-C. Huang)

Aims: Since apoptosis of macrophages induced by stress to the endoplasmic reticulum (ER) contributes to advanced atherosclerotic lesions, we sought to understand the effects of statins on the unfolded protein response (UPR).

Methods and results: We used pharmacological, biochemical, and siRNA (small interfering ribonucleic acid) approaches to determine the signalling cascades of statin-induced 78 kDa glucose-regulated protein (GRP78) gene transcription and its role in cytoprotection. Exposure of RAW264.7 macrophages to statins increased the expression of GRP78, activating transcription factor 6, X box protein-1, and phosphorylated eukaryotic translation initiation factor 2{alpha}, while it had no effect on CCAAT/enhancer binding protein-homologous protein. GRP78 induction was abolished by co-treatment with mevalonate and 1,2-bis(o-aminophenoxy)ethane-N, N, N',N'-tetraacetic acid, indicating the involvement of both 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase-dependent and -independent mechanisms. Studies on promoter activity measurements indicated that phosphoinositide turnover, cellular homologue of v-src (c-Src), protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and p38 are involved in upregulating GRP78 gene transcription. We also observed that elevation of intracellular Ca2+ and interruption of small G proteins are two bifurcated but cooperative signalling pathways for c-Src activation, leading to downstream activation of phospholipase C, PKC, ERK, and p38. Functionally we demonstrated that fluvastatin could protect macrophages from hypoxia-induced cell death through GRP78 induction.

Conclusion: We demonstrate a novel action of statins of inducing a cytoprotective UPR, providing new insights into the clinical potential of statins for ameliorating ER stress-related diseases.

KEYWORDS Statins; ER stress; GRP78; Macrophages; Signal transduction

Time for primary review: 44 days

{dagger} Wan-Wan Lin and Kuo-Chin Huang contributed equally to this work.


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