28
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pioglitazone stabilizes atherosclerotic plaque by regulating the Th17/Treg balance in AMPK-dependent mechanisms

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Pioglitazone (PIO), a thiazolidinediones drug, is a well-known anti-diabetic medicine, but its anti-atherosclerotic effects remain controversial. Thus it is important to investigate the effects of PIO on atherogenesis and the relevant mechanisms.

          Methods

          For in vitro studies, primary cultured or AMP-activated protein kinase (AMPK) inhibited splenocytes were treated with oxidized low density lipoprotein (ox-LDL) or ox-LDL plus PIO. Percentage of T helper 17 (Th17) and regulatory T (Treg) cells were determined by flow cytometry. Expression of AMPK, interleukin-17 (IL-17) and forkhead box P3 (FoxP3) were detected by Western blots. For in vivo studies, apolipoprotein E–deficient (apoE−/−) mice fed with western diet were treated with PIO or vehicle for 8 weeks respectively. Percentage of Th17 and Treg cells in spleen were measured by immunohistochemical analysis. The atherosclerotic lesions were analyzed using oil red O staining, and collagen types I and III in atherosclerotic lesions were stained by Sirius red. Expression of IL-17 and FoxP3 were determined by quantitative polymerase chain reaction.

          Results

          In cultured primary splenocytes, PIO dramatically inhibited Th17 and raised Treg. Intriguingly, pharmacological and genetic AMPK inhibitions abolished PIO-induced Treg elevation and Th17 inhibition. Moreover, PIO significantly induced AMPK phosphorylation, decreased IL-17 + and increased FoxP3 + cells in spleen of apoE−/− mice. Finally, PIO did not alter plaque area, but intriguingly, stabilized atherosclerotic plaque through collagen induction in apoE−/− mice. PIO treatment also improved Th17/Treg balance in atherosclerotic lesions.

          Conclusions

          PIO exhibits anti-atherosclerotic effects for stabilization of atherosclerotic plaque through regulating the Th17/Treg balance in an AMPK-dependent manner.

          Related collections

          Most cited references32

          • Record: found
          • Abstract: found
          • Article: not found

          The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways.

          AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (alpha) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase alpha or beta. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial.

            Carotid artery intima-media thickness (CIMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have suggested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear. To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT of the common carotid artery in patients with type 2 DM. Randomized, double-blind, comparator-controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006. The treatment period was 72 weeks (1-week follow-up). CIMT images were captured by a single ultrasonographer at 1 center and read by a single treatment-blinded reader using automated edge-detection technology. Participants were 462 adults (mean age, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonylurea, metformin, insulin, or a combination thereof. Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d) as an active comparator. Absolute change from baseline to final visit in mean posterior-wall CIMT of the left and right common carotid arteries. Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (-0.001 mm vs +0.012 mm, respectively; difference, -0.013 mm; 95% confidence interval, -0.024 to -0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, -0.024 mm; 95% confidence interval, -0.042 to -0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA(1c) value, and statin use. Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride. clinicaltrials.gov Identifier: NCT00225264
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.

              T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (IL)-17A in atherogenesis is not well defined. Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells, which in turn promote atherosclerosis. IL-17A was found to be elevated in the plasma and tissues of apolipoprotein E-deficient (Apoe(-/-)) mice. IL-17A-expressing T cells were significantly increased in the aortas, spleen, and lamina propria of aged Apoe(-/-) mice compared with age-matched C57BL/6 mice. IL-17A(+) T cells resided in both adventitia and aortas of aged Apoe(-/-) mice fed a chow diet. Elevated levels of IL-17A(+) T cells were also detected in the aortas of 21-week-old Apoe(-/-) mice fed a Western diet for 15 weeks. IL-17A(+) T cells were characterized as predominantly CD4(+) T helper 17 (Th17) cells and gammadelta(+) T cells. Blockade of IL-17A in Apoe(-/-) mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe(-/-) mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe(-/-) mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay. These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.
                Bookmark

                Author and article information

                Contributors
                tianyulingwater@163.com
                4056240@qq.com
                1533370441@qq.com
                105536588@qq.com
                2002wanglj@163.com
                colors727@163.com
                253505132@qq.com
                448596310@qq.com
                380867933@qq.com
                iyxdlyanjie@gmail.com
                53393656@qq.com
                +86-29-8532-3819 , zuyiyuan@mail.xjtu.edu.cn
                +86-29-8532-3819 , yue.wu@xjtu.edu.cn
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                30 October 2017
                30 October 2017
                2017
                : 16
                : 140
                Affiliations
                [1 ]GRID grid.452438.c, Department of Cardiology, , The First Affiliated Hospital of Xi’an Jiaotong University, ; 277 West Yanta Road, Xi’an, 710061 Shaanxi China
                [2 ]GRID grid.452438.c, Department of Vascular Surgery, , The First Affiliated Hospital of Xi’an Jiaotong University, ; Xi’an, 710061 Shaanxi China
                Author information
                http://orcid.org/0000-0003-1843-7430
                Article
                623
                10.1186/s12933-017-0623-6
                5663071
                29084546
                14031840-f516-4da4-ab44-108176c2753c
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 July 2017
                : 18 October 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81300226
                Award ID: 81025002
                Award Recipient :
                Categories
                Original Investigation
                Custom metadata
                © The Author(s) 2017

                Endocrinology & Diabetes
                pioglitazone,ampk,t cell,signaling,atherosclerosis
                Endocrinology & Diabetes
                pioglitazone, ampk, t cell, signaling, atherosclerosis

                Comments

                Comment on this article