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      Associations between PPARG polymorphisms and the risk of essential hypertension

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          Abstract

          Background

          Peroxisome proliferator-activated receptor gamma ( PPARG) plays an important role in the pathogenesis and maintenance of essential hypertension (EH). It has been suggested that polymorphisms of PPARG are associated with the risk of EH. However, findings to date remain controversial. To elucidate the associations between the PPARG Pro12Ala and C161T polymorphisms and EH risk, a meta-analysis was carried out.

          Methods

          A comprehensive literature search of PubMed, Embase, CNKI (Chinese National Knowledge Infrastructure), VIP and Wanfang databases was conducted. The pooled odds ratios (ORs) and 95% confidence interval (CI) were calculated to estimate the size of the effect using the random-effects model. At the same time, the pooled standardized mean difference (SMD) with 95% CI was used for the meta-analysis of the PPARG Pro12Ala polymorphism and blood pressure.

          Results

          Finally, Fifteen papers (seventeen studies) including 4,151 cases and 4,997 controls to evaluate the association of the PPARGPro12Ala polymorphism and EH risk, were included in this study. Overall, the results suggested that Ala allele was associated with the decreased EH risk (for allelic model, OR = 0.757, 95%CI: 0.624–0.918, P = 0.005; for dominant model, OR = 0.771, 95%CI: 0.627–0.946, P = 0.013). The subgroup analysis stratified by ethnicity showed that the significant association between the PPARG Pro12Ala polymorphism and EH was only detected in the Asian subgroup. There was no difference in blood pressure values between Ala carriers and non-carriers. For the C161T polymorphism, only 5 studies comprising 1,118 cases and 1,357 controls met the inclusion criteria. The overall results showed that the PPARG C161T polymorphism was not associated with the risk of EH. But in the subgroup analysis, we found that the PPARG C161T polymorphism significantly associated with the risk of EH in the Asian subgroup (for allelic model, OR = 0.719, 95% CI: 0.537–0.963, P = 0.027; for dominant model, OR = 0.653, 95% CI: 0.439–0.972, P = 0.036).

          Conclusion

          Our meta-analysis suggested that the PPARG polymorphisms might be associated with the risk of EH.

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          Most cited references33

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          Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease.

          Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/ß and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones.
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            Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes.

            Peroxisome proliferator-activated receptor (PPAR)-gamma plays an important role in adipogenesis. However, the functions of PPAR-gamma in differentiated adipocytes have remained unclear. The role of PPAR-gamma in mature 3T3-L1 adipocytes was therefore investigated by overexpression of a dominant negative mutant of this protein (PPAR-gamma-DeltaC) that lacks the 16 COOH-terminal amino acids and that has been shown to prevent the thiazolidinedione-induced differentiation of 3T3-L1 cells into adipocytes. Overexpression of PPAR-gamma-DeltaC in mature 3T3-L1 adipocytes by adenovirus gene transfer resulted in a decrease in both cell size and intracellular triglyceride content, an increase in the extent of lipolysis, and a reduction in the rate of free fatty acid uptake. Furthermore, overexpression of this mutant reduced the abundance of mRNAs for several key enzymes that contribute to triglyceride and free fatty acid metabolism as well as the amounts of GLUT4, insulin receptor, insulin receptor substrate (IRS), and C/EBPalpha mRNAs. It also reduced both the concentration of IRS2 and the insulin-stimulated glucose uptake. These results suggest that PPAR-gamma plays an important role in mature 3T3-L1 adipocytes at least in part by maintaining the expression of genes that confer the characteristics of mature adipocytes.
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              Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis.

              Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                20 July 2017
                2017
                : 12
                : 7
                : e0181644
                Affiliations
                [1 ] Department of Cardiology, Wujin hospital affiliated to Jiangsu University, Changzhou, Jiangsu Province, China
                [2 ] Department of Neurology, Huai’an second people’s hospital, the affiliated Huai’an hospital of Xuzhou Medical University, Huaian, Jiangsu Province, China
                [3 ] Department of Pathology and Molecular Medicine, McMaster University, Ontario, Canada
                Children's National Health System, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-16-45510
                10.1371/journal.pone.0181644
                5519177
                28727849
                7e42d49f-69af-477c-8232-d691f392b59c
                © 2017 Cai et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 December 2016
                : 5 July 2017
                Page count
                Figures: 10, Tables: 4, Pages: 17
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100007131, Changzhou Science and Technology Bureau;
                Award ID: 20160004
                Award Recipient :
                Funded by: Science and technology project of Wujin
                Award ID: WS201603
                Award Recipient :
                Funded by: Jiangsu Youth Medical Talents Project
                Award ID: QNRC2016310
                Award Recipient :
                Our manuscript was supported by Jiangsu Youth Medical Talents Project (QNRC2016310), the Changzhou Sci&Tech Program (Grant No.CJ20160004) and the Science and technology project of Wujin (WS201603).
                Categories
                Research Article
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                People and Places
                Population Groupings
                Ethnicities
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Genotyping
                Research and Analysis Methods
                Molecular Biology Techniques
                Genotyping
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                People and Places
                Population Groupings
                Ethnicities
                Chinese People
                Biology and Life Sciences
                Evolutionary Biology
                Population Genetics
                Genetic Polymorphism
                Biology and Life Sciences
                Genetics
                Population Genetics
                Genetic Polymorphism
                Biology and Life Sciences
                Population Biology
                Population Genetics
                Genetic Polymorphism
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