Regulatory T cells contribute to rosuvastatin-induced cardioprotection against ischemia-reperfusion injury

Ke, Dan; Fang, Jun; Lin, Fan; Chen, Zhaoyang; Chen, Lianglong

doi:10.1097/mca.0b013e3283608c12

Cited by 40 publications

(30 citation statements)

References 3 publications

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“…In fact, by using a mouse model of chronic asthma, Carson et al (26) showed that the resolution of inflammation is correlated with the accumulation of Treg cells in lung-draining hilar lymph nodes. On the basis of increase of Tregs in MLN, we found an increase of Foxp3 mRNA expression in this compartment (Figure 3A), confirming the ATV effect on Tregs, as demonstrated in the previous studies of murine models of acute inflammation (37, 42). We characterized the Treg population by measuring the expression of several molecules, such as OX-40, GITR, and PD-1, whose suppressive capacities have also been implicated during allergic asthma.…”

Section: Discussionsupporting

confidence: 89%

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

et al. 2016

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Regulatory T cells (Tregs) play an important role by controlling allergic inflammation of airways. Recently, it has been shown that statins have immunomodulatory properties, probably mediated by their effects on Tregs. Therefore, we evaluated the in vivo effect of atorvastatin (ATV) on Tregs and its association with the inflammatory process in a model of allergic asthma. BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with intranasal OVA. ATV (40 mg/kg) was delivered by daily intraperitoneal injection for 7 or 15 days before each OVA challenge. ATV treatment for 7 days increased the frequency of Tregs in mediastinal lymph nodes (MLN) and the interleukin (IL)-10 in lungs. After 15 days of treatment, ATV increased the percentage of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+) and programmed cell death protein 1 (PD-1+) Tregs in the lung, without enhancing their suppressive activity, but also increased the percentage of conventional T cells expressing GITR+, PD1+, and OX-40 (tumor necrosis factor receptor superfamily member 4). Although no significant changes were observed in the number of inflammatory cells in the bronchoalveolar lavage (BAL), OVA-specific immunoglobulin E in the serum, and type 2 helper (Th2) cytokines in the lungs, there was a significant decrease of peribronchial inflammation that negatively correlated with the Tregs in MLN and the concentration of IL-10 in the lung. These results suggest that ATV has an immunomodulatory role possibly mediated by their effects on Tregs, which could contribute to the control of inflammation during allergic asthma. Further studies are necessary to elucidate the contribution of Treg to immunomodulatory action of statins in the context of allergic asthma.

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Section: Discussionsupporting

confidence: 89%

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

et al. 2016

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“…Restoration of the Treg balance appears to be an important mechanism of action of GA in MS [29,30,37,38]. Interestingly, there are only limited data suggesting that statins may promote expansion of Tregs [39-41]. We found that neither treatment initiated prior to disease induction nor following EAE onset altered the frequency of CD4 + CD25 + Foxp3 + Tregs in diseased mice.…”

Section: Discussionmentioning

confidence: 72%

Neither T-helper type 2 nor Foxp3+regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity

Weber

Prod’homme

Youssef

et al. 2014

J Neuroinflammation

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Oral atorvastatin has prevented or reversed paralysis in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE), and reduced development of new MS lesions in clinical trials. Besides inhibiting development of encephalitogenic T cells, atorvastatin treatment of EAE has been associated with an induction of anti-inflammatory myelin-reactive T-helper type (Th)-2 cells. To investigate the clinical significance of atorvastatin-mediated Th2 differentiation, we first evaluated atorvastatin treatment in interleukin (IL)-4 green fluorescent protein-enhanced transcript (4-GET) reporter mice. Atorvastatin treatment failed to induce IL-4-producing Th2 cells in vivo; however, when T cells from atorvastatin-treated 4-GET mice were reactivated in vitro, T cells preferentially differentiated into Th2 cells, while antigen-specific T-cell proliferation and secretion of proinflammatory cytokines (interferon gamma, IL-17, tumor necrosis factor and IL-12) were reduced. Oral atorvastatin also prevented or reversed EAE in signal transducer and activator of transcription 6-deficient (STAT6−/−) mice, which cannot generate IL-4-producing Th2 cells. Further, atorvastatin treatment did not induce or expand Foxp3+ regulatory T cells in either wild-type or STAT6−/− mice. In vivo proliferation of T cells, as measured by incorporation of bromodeoxyuridine, was inhibited in atorvastatin-treated wild-type and STAT6−/− mice. These data imply that atorvastatin ameliorates central nervous system autoimmune disease primarily by inhibiting proliferation of proinflammatory encephalitogenic T cells, and not simply through induction of anti-inflammatory Th2 cells. This cytostatic effect may be a relevant mechanism of action when considering use of statins in MS and other inflammatory conditions.

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“…It was reported that rosuvastatin may have protective effects in I/R injury and these effects could have been mediated by immunomodulatory and anti-inflammatory effects 7,17,23. Kuhn et al 24 showed that myocardial function improved with rosuvastatin administration for seven days prior to cardiopulmonary bypass surgery.…”

Section: Discussionmentioning

confidence: 99%

Effects of rosuvastatin on ADMA, rhokinase, NADPH oxidase, caveolin-1, hsp 90 and NFkB levels in a rat model of myocardial ischaemia-reperfusion : cardiovascular topic

Burma

Onat

Uysal

et al. 2014

CVJA

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SummaryAimEndothelial dysfunction, oxidative stress and inflammation are among the most important mechanisms of ischaemia–reperfusion (I/R) injury. Besides their cholesterol-lowering effects, statins are known to provide protection against myocardial dysfunction and vascular endothelial injury via nitric oxide-dependent mechanisms. The aim of this study was to investigate the effects of rosuvastatin on certain intermediates involved in the generation of nitric oxide (asymmetrical dimethyl arginin, ADMA, caveolin-1 and hsp 90), oxidative stress (rhokinase, NADPH oxidase) and inflammation (NFkB), using an in vivo model of myocardial infarction in the rat.MethodsAdult male Sprague Dawley rats were divided into three groups (control, I/R and I/R after 15 days of rosuvastatin administration). Reperfusion was applied for 120 min following left anterior descending coronary artery ischaemia for 30 min. Caveolin-1, hsp 90 and NFkB levels were evaluated with the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and ADMA, rhokinase and NADPH oxidase levels were evaluated with ELISA.ResultsWhile NFkB and hsp 90 levels were higher in the I/R group, their levels were significantly lower in the rosuvastatin group. While ADMA and NADPH oxidase levels significantly increased with I/R, they were lower in the rosuvastatin-treated group, but not statistically significant. Rhokinase levels were significantly lower in the rosuvastatin group. Caveolin-1 levels were not different between the groups.ConclusionOur results suggest that ADMA, rhokinase, NADPH oxidase, hsp 90 and NFkB could facilitate I/R injury, and rosuvastatin significantly reduced levels of these parameters. These results indicate that rosuvastatin may have a protective role in I/R injury via mechanisms targeting inflammation, endothelial dysfunction and oxidative stress.

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Regulatory T cells contribute to rosuvastatin-induced cardioprotection against ischemia-reperfusion injury

Abstract: RSV pretreatment was associated with more Treg accumulation, less inflammatory response, and myocardial injury, suggesting that such cardioprotection against IRI was partially mediated by Treg-negative modulation of inflammation response, probably through the HMG-CoA reductase pathway.

Cited by 40 publications

References 3 publications

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma

Neither T-helper type 2 nor Foxp3+regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity

Effects of rosuvastatin on ADMA, rhokinase, NADPH oxidase, caveolin-1, hsp 90 and NFkB levels in a rat model of myocardial ischaemia-reperfusion : cardiovascular topic

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