Probucol Prevents Atrial Remodeling by Inhibiting Oxidative Stress and TNF‐α/NF‐κB/TGF‐β Signal Transduction Pathway in Alloxan‐Induced Diabetic Rabbits

Fu, Hai-Xia; Li, Guangping; Liu, Changle; Li, Jian; Wang, Xinghua; Cheng, Lijun; Liu, Tong

doi:10.1111/jce.12540

Cited by 58 publications

(54 citation statements)

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“…Autonomic dysfunction in DM patients can be caused by hyperglycemia‐mediated pathways such as formation of advanced glycation end products (AGEs), elevated oxidative or nitrosative stress with increased production of free radicals 19. Our previous work has reported that in the diabetic atria, electrical remodeling took the form of characterized by conduction slowing, increased AERP dispersion and prolonged action potential duration, in an absence of frequency‐dependent shortening of action potential duration, and increased amplitude of action potential duration alternans 21, 26. These would be expected to predispose to re‐entrant arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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BackgroundThere are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes.Methods and ResultsNinety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol‐treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage‐clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial‐related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment.ConclusionsAllopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM‐related increases in oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Yang

Zhao

Qiu

et al. 2018

JAHA

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“…Additionally, the serum concentrations of inflammatory cytokines (CRP, IL-6, IL-18, and TNF-α) are markedly lower in probucol-treated atherosclerotic rabbits [24] . The expression of TNF-α, TGF-β, and HSP70 is also significantly downregulated by probucol treatment in alloxaninduced diabetic rabbits [23] . Consistent with these reports, our findings provide evidence that treatment with probucol significantly reduced IL-1β and IL-6 production in addition to IL-1β and IL-6 gene expression in LPS-activated microglial BV2 cells (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the identification of novel agents that regulate neuroinflammation by inhibiting microglial activation is regarded as a significant strategy for the treatment of ischemic stroke. Several animal studies have demonstrated that probucol exerts beneficial effects via anti-inflammation mechanisms in aging mice [19,20] , focal cerebral ischemic mice [8,9] , heart failure rats [21,22] , diabetic rabbits [23] and atherosclerotic rabbits [24] . Probucol has also been demonstrated to prevent atherogenesis via the induction of the anti-inflammatory enzyme heme oxygenase-1 independently of lipid oxidation and cholesterol reduction in models of atherosclerosis, restenosis and type 2 diabetes [32] .…”

Section: Discussionmentioning

confidence: 99%

“…Probucol also dramatically retards atherosclerosis in hyperlipidemic animals [16][17][18] . Furthermore, probucol has been demonstrated to posse the capacity to attenuate inflammation in animal models of aging [19,20] , focal cerebral ischemia [8,9] and ischemic myocardial injury [21,22] , as well as in diabetic [23] and atherosclerotic rabbits [24] . Based on these reports, probucol may be useful for the treatment of ischemic stroke with hyperlipidemia via reductions in cholesterol and neuroinflammation.…”

Section: Original Articlementioning

confidence: 99%

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Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

et al. 2016

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Aim: Increasing evidence suggests that probucol, a lipid-lowering agent with anti-oxidant activities, may be useful for the treatment of ischemic stroke with hyperlipidemia via reduction in cholesterol and neuroinflammation. In this study we examined whether probucol could protect against brain ischemic injury via anti-neuroinflammatory action in normal and hyperlipidemic mice. Methods: Primary mouse microglia and murine BV2 microglia were exposed to lipopolysaccharide (LPS) for 3 h, and the release NO, PGE2, IL-1β and IL-6, as well as the changes in NF-κB, MAPK and AP-1 signaling pathways were assessed. ApoE KO mice were fed a high-fat diet containing 0.004%, 0.02%, 0.1% (wt/wt) probucol for 10 weeks, whereas normal C57BL/6J mice received probucol (3, 10, 30 mg·kg -1 ·d -1 , po) for 4 d. Then all the mice were subjected to focal cerebral ischemia through middle cerebral artery occlusion (MCAO). The neurological deficits were scored 24 h after the surgery, and then brains were removed for measuring the cerebral infarct size and the production of pro-inflammatory mediators. Results: In LPS-treated BV2 cells and primary microglial cells, pretreatment with probucol (1, 5, 10 μmol/L) dose-dependently inhibited the release of NO, PGE2, IL-1β and IL-6, which occurred at the transcription levels. Furthermore, the inhibitory actions of probucol were associated with the downregulation of the NF-κB, MAPK and AP-1 signaling pathways. In the normal mice with MCAO, preadministration of probucol dose-dependently decreased the infarct volume and improved neurological function. These effects were accompanied by the decreased production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6). In ApoE KO mice fed a high-fat diet, pre-administration of 0.1% probucol significantly reduced the infarct volume, improved the neurological deficits following MCAO, and decreased the total-and LDL-cholesterol levels. Conclusion: Probucol inhibits LPS-induced microglia activation and ameliorates cerebral ischemic injury in normal and hyperlipidemic mice via its anti-neuroinflammatory actions, suggesting that probucol has potential for the treatment of patients with or at risk for ischemic stroke and hyperlipidemia.

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“…Taken together, our data indicate that carbatonides might have a potential as drugs intended to treat DM complications. KEY WORDS: 1,4-dihydropyridine derivatives; diabetes mellitus; DNA damage; free radical scavengers; nitric oxide synthases New remedies for treatment of type one diabetes mellitus (T1DM) complications are sought among compounds with antioxidant activities (1,2). Following this logic, we have chosen some representatives of group of 1,4-dihydropyridine (1,4-DHP) derivatives synthesised in the Latvian Institute of Organic Synthesis (see Table 1 for structures).…”

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confidence: 99%

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

Ošiņa

Ļeonova

Isajevs

et al. 2017

Archives of Industrial Hygiene and Toxicology

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Studies on the pathogenesis of diabetes mellitus complications indicate that the compounds reducing free radicals and enhancing DNA repair could be prospective as possible remedies. Carbatonides, the disodium-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) derivatives, were tested for these properties. EPR spectroscopy showed that metcarbatone was an effective scavenger of hydroxyl radicals produced in the Fenton reaction, etcarbatone, and propcarbatone were less effective, styrylcarbatone was ineffective. UV/VIS spectroscopy revealed that styrylcarbatone manifested a hyperchromic effect when interacting with DNA, while all other carbatonides showeda hypochromic effect. Rats with streptozotocin induced type 1 DM were treated with metcarbatone, etcarbatone or styrylcarbatone (all compounds at doses 0.05 mg kg -1 or 0.5 mg kg -1 ) nine days after the DM approval. Gene expression levels in kidneys and blood were evaluated by quantitative RT-PCR; protein expression -immunohistochemically in kidneys, heart, sciatic nerve, and eyes; DNA breakage -by comet assay in nucleated blood cells. Induction of DM induced DNA breaks; metcarbatone and styrylcarbatone (low dose) alleviated this effect. Metcarbatone and etcarbatone up-regulated mRNA and protein of eNOS in kidneys of diabetic animals; etcarbatone also in myocardium. Etcarbatone reduced the expression of increased iNOS protein in myocardium, nerve, and kidneys. iNos gene expression was up-regulated in kidneys by etcarbatone and metcarbatone in diabetic animals. In blood, development of DM increased iNos gene expression; etcarbatone and metcarbatone normalised it. Etcarbatone up-regulated the expression of H2AX in kidneys of diabetic animals but decreased the production of c-PARP1. Taken together, our data indicate that carbatonides might have a potential as drugs intended to treat DM complications.

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Probucol Prevents Atrial Remodeling by Inhibiting Oxidative Stress and TNF‐α/NF‐κB/TGF‐β Signal Transduction Pathway in Alloxan‐Induced Diabetic Rabbits

Abstract: Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.

Cited by 58 publications

References 37 publications

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

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