ß-Hydroxybutyrate inhibits cardiac microvascular collagen 4 accumulation by attenuating oxidative stress in streptozotocin-induced diabetic rats and high glucose treated cells.
Eur J Pharmacol
; 899: 174012, 2021 May 15.
Article
em En
| MEDLINE
| ID: mdl-33727057
ABSTRACT
Accumulation of collagen 4 (COL4) and thickened basement membrane are features of diabetic cardiac microvascular fibrosis that may be induced by oxidative stress. The ketone body ß-hydroxybutyrate exhibits various cardiovascular protective effects, however its mechanism remains to be clarified. In the current study, the effects of ß-hydroxybutyrate on cardiac microvascular fibrosis and COL4 accumulation were evaluated in streptozotocin-induced diabetic rats and in high glucose (HG) treated human cardiac microvascular endothelial cells (HCMECs). Generations of inducible nitric oxide synthase (iNOS) and copper-zinc superoxide dismutase (Cu/Zn-SOD), and the amount of nitrotyrosine (NT) were measured in vivo and in vitro. Ten weeks of ß-hydroxybutyrate treatment (160, 200 and 240 mg/kg/d) attenuated cardiac microvascular fibrosis and inhibited cardiac COL4 generation and microvascular distribution in diabetic rats. Furthermore, ß-hydroxybutyrate promoted cardiac Cu/Zn-SOD generation and reduced NT content, without reducing iNOS generation in diabetic rats. In HCMECs, stimulation with HG induced excess generation of COL4 via peroxynitrite. ß-Hydroxybutyrate treatment (2, 4, 6 mM) attenuated HG-stimulated COL4 accumulation in a concentration-dependent manner. Similarly, 4 mM ß-hydroxybutyrate promoted Cu/Zn-SOD generation and reduced NT content, without affecting excess iNOS generation in HG-stimulated HCMECs. In conclusion, this study showed that ß-hydroxybutyrate promoted Cu/Zn-SOD generation, reduced peroxynitrite and inhibited cardiac microvascular COL4 accumulation in diabetes.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Estresse Oxidativo
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Vasos Coronários
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Ácido 3-Hidroxibutírico
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Colágeno Tipo IV
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Miócitos Cardíacos
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Diabetes Mellitus Experimental
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Microvasos
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Cardiomiopatias Diabéticas
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Antioxidantes
Tipo de estudo:
Etiology_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2021
Tipo de documento:
Article