Atorvastatin Downregulates Monocyte CD36 Expression, Nuclear NFκB and TNFα Levels in Type 2 Diabetes

Mandosi, Elisabetta; Fallarino, Mara; Gatti, Alessandra; Carnovale, Anna; Rossetti, M.; Lococo, Emanuela; Buchetti, Barbara; Filetti, Sébastiano; Lenti, Luisa; Morano, Susanna

doi:10.5551/jat.2956

Cited by 45 publications

(43 citation statements)

References 29 publications

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“…Furthermore, the anti-apoptotic mechanism of ATOR may partially explain its therapeutic effects in some diseases, including ischemic stroke and Alzheimer’s Disease, which are both associated with apoptosis [24–26] and are effectively treated with ATOR [27, 28]. Previous studies reported that NF-κB activation was indirectly regulated by GSK-3β [23] and that NF-κB activity was inhibited by ATOR in a variety of cell types [29] and animal models [30, 31], and our study further supports the negative regulation of NF-κB by ATOR.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

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Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3β-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3β was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3β expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3β and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg−1-d−1, significantly suppressed GSK-3β activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3β-PP2A-NF-κB signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Ren

Zuo

et al. 2016

PLoS ONE

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“…Furthermore, atorvastatin was recently shown to be even more effective than diclofenac in decreasing joint inflammation and hyperalgesia in a rat model of arthritis (37), and in reducing TNF-α production in lipopolysaccharideactivated monocytes from diabetic patients (38). Another statin, simvastatin, was reported to prevent the increase of iNOS concentration after ischemia/reperfusion injury in the rat liver (39).…”

Section: Discussionmentioning

confidence: 99%

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

Gonçalves

Calou

Siqueira

et al. 2011

Braz J Med Biol Res

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Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid-lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g) and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20-25 g), which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan), at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively). Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation) reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively) and second phase (73, 57, and 66% inhibition of licking time, respectively). The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc). Lovastatin (0.01, 0.1, and 1 µg/mL) inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils) infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-α (TNF-α) and the inducible form of nitric oxide synthase (iNOS) activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin.

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“…Relatedly, we also found hyperlipidemia to be associated with Charcot foot. Treatment of CAD with 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase inhibitors (i.e., “statins”) has also been described to have an anti-inflammatory effect [33, 34]. CAD has not been described in prior Charcot foot multivariate models [4, 5].…”

Section: Discussionmentioning

confidence: 99%

Data Mining for Identifying Novel Associations and Temporal Relationships with Charcot Foot

Munson

Wrobel

Holmes

et al. 2014

Journal of Diabetes Research

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Introduction. Charcot foot is a rare and devastating complication of diabetes. While some risk factors are known, debate continues regarding etiology. Elucidating other associated disorders and their temporal occurrence could lead to a better understanding of its pathogenesis. We applied a large data mining approach to Charcot foot for elucidating novel associations. Methods. We conducted an association analysis using ICD-9 diagnosis codes for every patient in our health system (n = 1.6 million with 41.2 million time-stamped ICD-9 codes). For the current analysis, we focused on the 388 patients with Charcot foot (ICD-9 713.5). Results. We found 710 associations, 676 (95.2%) of which had a P value for the association less than 1.0 × 10−5 and 603 (84.9%) of which had an odds ratio > 5.0. There were 111 (15.6%) associations with a significant temporal relationship (P < 1.0 × 10−3). The three novel associations with the strongest temporal component were cardiac dysrhythmia, pulmonary eosinophilia, and volume depletion disorder. Conclusion. We identified novel associations with Charcot foot in the context of pathogenesis models that include neurotrophic, neurovascular, and microtraumatic factors mediated through inflammatory cytokines. Future work should focus on confirmatory analyses. These novel areas of investigation could lead to prevention or earlier diagnosis.

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Atorvastatin Downregulates Monocyte CD36 Expression, Nuclear NFκB and TNFα Levels in Type 2 Diabetes

Cited by 45 publications

References 29 publications

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3β-PP2Ac-NF-κB Signaling Axis

In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents

Data Mining for Identifying Novel Associations and Temporal Relationships with Charcot Foot

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