Dimethyl fumarate ameliorates diabetes-associated vascular complications through ROS-TXNIP-NLRP3 inflammasome pathway

Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3...

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Published in:Life sciences (1973) 2020-09, Vol.256, p.117887, Article 117887
Main Authors: Amin, Fatma M., Abdelaziz, Rania R., Hamed, Mohamed F., Nader, Manar A., Shehatou, George S.G.
Format: Article
Language:English
Subjects:
Acetylcholine
Aorta
Attenuation
Bioavailability
Blood glucose
Caspase-3
Complications
Contractility
Diabetes
Diabetes mellitus
Dimethyl fumarate
eNOS
High density lipoprotein
IL-1β
Inflammasomes
Morbidity
mRNA
NF-κB protein
Nitric-oxide synthase
NLRP3
Phenylephrine
Potassium chloride
Proteins
Rodents
ROS
Streptozocin
STZ
TNF-α
Transforming growth factor-b1
Tumor necrosis factor-α
TXNIP
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Summary:Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3 inflammasome pathway. Two weeks after induction of diabetes (via a single injection of 50 mg/kg STZ, i.p.), diabetic rats were administered either DMF (25 mg/kg/day) or its vehicle for further eight weeks. Age-matched normal and DMF-administered non-diabetic rats served as controls. DMF treatment elicited a mild ameliorative effect on diabetic glycemia. DMF reduced serum TG and AGE levels and enhanced serum HDL-C concentrations in diabetic rats. Moreover, DMF significantly diminished aortic levels of ROS and MDA and restored aortic GSH, SOD and Nrf2 to near-normal levels in STZ rats. Aortic mRNA levels of TXNIP, NLRP3 and NF-κB p65 in diabetic rats were significantly reduced by DMF treatment. Serum and aortic protein levels of TXNIP and aortic contents of IL-1β, iNOS, NLRP3 and TGF-β1 were significantly lower in DMF-diabetic animals than non-treated diabetic rats. Furthermore, protein expression of TNF-α and caspase-3 in diabetic aortas was greatly attenuated by DMF administration. DMF enhanced eNOS mRNA and protein levels and increased bioavailable NO in diabetic aortas. Functionally, DMF attenuated contractile responses of diabetic aortic rings to KCl and phenylephrine and enhanced their relaxant responses to acetylcholine. DMF also mitigated diabetes-induced fibrous tissue proliferation in aortic tunica media. Collectively, these findings demonstrate that DMF offered vasculoprotective influences on diabetic aortas via attenuation of ROS-TXNIP-NLRP3 inflammasome pathway.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2020.117887