Endothelial protective genes induced by statin are mimicked by ERK5 activation as triggered by a drug combination of FTI-277 and GGTI-298.
Biochim Biophys Acta
; 1850(7): 1415-25, 2015 Jul.
Article
em En
| MEDLINE
| ID: mdl-25829196
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. GENERALSIGNIFICANCE:
The combinatorial FTI-277 and GGTI-298 drug regimen provides a promising alternative avenue for endothelial protection without myopathy.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Inibidores de Hidroximetilglutaril-CoA Redutases
/
Células Endoteliais
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Proteína Quinase 7 Ativada por Mitógeno
/
Metionina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biochim Biophys Acta
Ano de publicação:
2015
Tipo de documento:
Article