The histone deacetylase inhibitor tubacin mitigates endothelial dysfunction by up-regulating the expression of endothelial nitric oxide synthase.
J Biol Chem
; 294(51): 19565-19576, 2019 12 20.
Article
em En
| MEDLINE
| ID: mdl-31719145
ABSTRACT
Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo We found that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found that these effects were not mediated by tubacin's inhibitory effect on HDAC6 activity, but rather were due to its ability to stabilize eNOS mRNA transcripts. Consistent with these findings, tubacin also inhibited proinflammatory cytokine-induced degradation of eNOS transcripts and impairment of endothelium-dependent relaxation in the mouse aorta. Furthermore, we found that tubacin-induced up-regulation in eNOS expression in vivo is associated with improved endothelial function in diabetic db/db mice and with a marked attenuation of ischemic brain injury in a murine stroke model. Our findings indicate that tubacin exhibits potent eNOS-inducing effects and suggest that this compound might be useful for the prevention or management of endothelial dysfunction-associated cardiovascular diseases.
Palavras-chave
cardiovascular disorder, tubulin acetylation inducer (tubacin); cytoskeleton; diabetes; endothelial cells; endothelial dysfunction; endothelial nitric oxide synthase (eNOS); endothelium; gene regulation; histone acetylase; histone deacetylase 6 (HDCA6); inflammation; nitric oxide; nitric oxide synthase; stroke
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endotélio Vascular
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Óxido Nítrico Sintase Tipo III
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Inibidores de Histona Desacetilases
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Desacetilase 6 de Histona
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Ácidos Hidroxâmicos
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Anilidas
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Óxido Nítrico
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article