Endothelial protective genes induced by statin are mimicked by ERK5 activation as triggered by a drug combination of FTI-277 and GGTI-298.

Abstract

BACKGROUND:

Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing cardiovascular diseases, however, the therapeutic utility of these drugs is limited by myotoxicity. Here, we explored the mechanism of statin-mediated activation of ERK5 in the human endothelium with the goal of identifying compounds that confer endothelial protection but are nontoxic to muscle.

METHODS:

An ERK5-one hybrid luciferase reporter transfected into COS-7 cells with pharmacological and molecular manipulations dissected the signaling pathway leading to statin activation of ERK5. qRT-PCR of HUVEC cells documented the transcriptional activation of endothelial-protective genes. Lastly, morphological and cellular ATP analysis, and induction of atrogin-1 in C2C12 myotubes were used to assess statin-induced myopathy.

RESULTS:

Statin activation of ERK5 is dependent on the cellular reduction of GGPPs. Furthermore, we found that the combination of FTI-277 (inhibitor of farnesyl transferase) and GGTI-298 (inhibitor of geranylgeranyl transferase I) mimicked the statin-mediated activation of ERK5. FTI-277 and GGTI-298 together recapitulated the beneficial effects of statins by transcriptionally upregulating anti-inflammatory mediators such as eNOS, THBD, and KLF2. Finally, C2C12 skeletal myotubes treated with both FTI-277 and GGTI-298 evoked less morphological and cellular changes recognized as biomarkers of statin-associated myopathy.

CONCLUSIONS:

Statin-induced endothelial protection and myopathy are mediated by distinct metabolic intermediates and co-inhibition of farnesyl transferase and geranylgeranyl transferase I confer endothelial protection without myopathy.

GENERAL SIGNIFICANCE:

The combinatorial FTI-277 and GGTI-298 drug regimen provides a promising alternative avenue for endothelial protection without myopathy.

• Authors: Uyen B Chu, Tyler Duellman, Sara J Weaver, Yunting Tao, Jay Yang
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1850 Issue 7 Pg. 1415-25 (Jul 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25829196 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Benzamides
• Enzyme Inhibitors
• FTI 277
• GGTI 298
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• KLF2 protein, human
• Kruppel-Like Transcription Factors
• THBD protein, human
• Thrombomodulin
• Methionine
• Nitric Oxide Synthase Type III
• Mitogen-Activated Protein Kinase 7

Topics

• Animals
• Benzamides (pharmacology)
• Blotting, Western
• COS Cells
• Cell Line
• Cells, Cultured
• Chlorocebus aethiops
• Endothelial Cells (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Methionine (analogs & derivatives, pharmacology)
• Mice
• Mitogen-Activated Protein Kinase 7 (genetics, metabolism)
• Muscle Fibers, Skeletal (cytology, drug effects, metabolism)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Phosphorylation (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Thrombomodulin (genetics, metabolism)