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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses peroxisome proliferator-activated receptors (PPARs) in an overview of the current knowledge concerning the effects of PPAR agonists on the vascular bed.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eischemia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ecerebrovascular disease genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ecerebrovascular disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EEyal Leibovitz, MD, McGill University, Montreal, Quebec, Canada, gave a brief tutorial on PPARs (peroxisome proliferator-activated receptors) and presented an overview of the current knowledge concerning the effects of PPAR agonists on the vascular bed.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EPeroxisomes are intracellular organelles that are predominant in nearly all mammalian cells. PPARs received their name when it was shown that the activation of these receptors was associated with proliferation of peroxisomes in rodents. There are 3 types of PPARs: PPAR\u03b1, PPAR\u03b3, and PPAR\u03b2. The natural activators of the PPARs are fatty acids, but some prostaglandins and leukotrienes also activate them, and they can also be activated by synthetic compounds, including fibrates, which activate PPAR\u03b1 and are an accepted treatment for dyslipidemia, and the thiazolidinediones (TZDs), which activate PPAR\u03b3 and are an accepted treatment for type 2 diabetes mellitus. PPAR\u03b2\/\u03b4 activators are experimental and are not used clinically.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EBoth PPAR\u03b1 and \u03b3 are expressed in human vascular endothelial cells [Delerive P et al. \u003Cem\u003ECirc Res\u003C\/em\u003E 1999], and animal studies have shown that PPAR\u03b1 and \u03b3 may exert vascular protective effects in hypertension and other forms of cardiovascular disease by interfering with signaling pathways that lead to endothelial dysfunction, vascular remodeling, inflammation, oxidative stress, and the growth and progression of atherosclerosis [Diep et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2002; Diep et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2002; Collins AR et al. \u003Cem\u003EATVB\u003C\/em\u003E 2001].\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EClinical evidence regarding the vascular effects of PPAR activators come from studies of dyslipidemia (PPAR\u03b1 activators) and diabetes mellitus (PPAR\u03b3 activators). The use of fibrates has been clearly shown to reduce morbidity and mortality among diabetic dyslipidemic patients; however, the results among nondiabetic dyslipidemic individuals, especially those with low HDL levels, are not as clear. The results with PPAR\u03b3 activators, although effective in controlling metabolic aspects of diabetes, remain controversial from the point of view of cardiovascular protection.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EAlthough the use of selective PPAR\u03b3 activators may exert vascular protective effects in hypertension or other forms of cardiovascular disease, Dr. Leibovitz concluded with a caution that one of the PPAR\u03b3 agonists has been associated with a significant increase in the risk of myocardial infarction and heart failure, and with an important but not statistically significant increase in the risk of death from cardiovascular causes [Nissen SE, Wolski K. \u003Cem\u003ENEJM 2007;\u003C\/em\u003E Nissen SE et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EFrank M. Faraci, PhD, University of Iowa, Iowa City, IA, and his colleagues have been studying mice that have been genetically altered to express dominant-negative mutations of the human PPAR\u03b3 gene (PPAR\u03b3 P465L, for example). In these \u201chumanized\u201d mice the subsequent interference with PPAR\u03b3 signaling caused selective endothelial dysfunction in both cerebral arteries and arterioles. The impact of PPAR\u03b3 interference was prominent in the cerebral circulation and the aorta was relatively normal in these mice.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ELevels of superoxide (an oxygen-derived free radical) were increased in cerebral arterioles, and impaired endothelial function could be restored to normal with a scavenger of superoxide in PPAR\u03b3 P465L mice, suggesting that mechanisms that account for impairment of cerebral vascular function following interference with PPAR\u03b3 involve oxidative stress.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe implications of these findings extend far beyond regulation of vascular tone, because the endothelium affects vascular structure, blood cells, and neuronal function. Other studies that have been conducted by Dr. Faraci and colleagues have shown that interference with PPAR\u03b3, either systemically or specifically in vascular muscle, produces vascular hypertrophy and inward growth of cerebral arterioles. These findings indicate that PPAR\u03b3 normally inhibits vascular growth and inward vascular remodelling\u2014effects that have a significant impact on local hemodynamics.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EFuture research will focus on identifying the mechanisms that promote oxidative stress and alter vascular growth, further defining the cell-specific role for PPAR\u03b3, and determining whether overexpression of wild-type PPAR\u03b3 protects against vascular disease.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EJaroslaw Aronowski, PhD, University of Texas, Houston, TX, reviewed the results of several animal studies that focused on the neuroprotective, cytoprotective, and neuroinflammation role of PPAR\u03b3 following an intracerebral hemorrhage (ICH).\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EEmploying an excitotoxic, ischemia-like (oxygen-glucose-deprivation; OGD), or oxidative stress (hydrogen peroxide; H2O2) injury to neurons, Aronowski and colleagues have shown that PPAR\u03b3 significantly reduces neuronal death (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). This neuroprotective effect was linked to increased PPAR\u03b3 DNA-binding activity [Brain Res. 2006].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022PPAR\u0026#x3B3; Activator Reduces ODG- and H2O2-Mediated Damage.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-656388094\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;PPAR\u0026#x3B3; Activator Reduces ODG- and H\u0026amp;lt;sub\u0026amp;gt;2\u0026amp;lt;\/sub\u0026amp;gt;O\u0026amp;lt;sub\u0026amp;gt;2\u0026amp;lt;\/sub\u0026amp;gt;-Mediated Damage.\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/10982\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003EPPAR\u03b3 Activator Reduces ODG- and H\u003Csub\u003E2\u003C\/sub\u003EO\u003Csub\u003E2\u003C\/sub\u003E-Mediated Damage.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EIn another study, injection of 15d-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a proposed endogenous PPAR\u03b3 agonist, into the locus of striatal hematoma increased PPAR\u03b3 DNA-binding activity, the expression of catalase messenger ribonucleic acid (mRNA), and protein in the perihemorrhagic area. Additionally, 15d-PGJ(2) significantly reduced nuclear factor-kappaB (NF\u03baB) activation and prevented neutrophil infiltration, reduced neuronal death, and reduced behavioral dysfunction produced by the ICH [Zhao X et al. \u003Cem\u003EJ Cereb Blood Flow Metab\u003C\/em\u003E 2006].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EThe PPAR\u03b3 agonist rosiglitazone stimulated primary microglia in culture toward phagocytosis of red blood cells. Rosiglitazone also promoted hematoma resolution, decreased neuronal damage, and improved functional recovery in a mouse ICH model. PPAR\u03b3 activators significantly increase PPAR\u03b3-regulated gene expression (catalase and CD36) and reduce proinflammatory gene expression [Zhao X et al. Ann Neurol 2007]. Intraventricular injection of ciglitazone or 15d-PGJ(2) into ischemic rat brains significantly increased the PPAR\u03b3 DNA-binding activity and reduced infarction volume at 24h after reperfusion [\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E; Ou Z et al. Brain Res 2006].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Intraventricular Injection of Ciglitazone Reduced Infarct Volume 24h After Reperfusion.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-656388094\u0022 data-figure-caption=\u0022Intraventricular Injection of Ciglitazone Reduced Infarct Volume 24h After Reperfusion.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/1\/18\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/10985\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-16\u0022 class=\u0022first-child\u0022\u003EIntraventricular Injection of Ciglitazone Reduced Infarct Volume 24h After Reperfusion.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EAll of these results suggest that PPAR\u03b3 may be beneficial in protecting brain cells from ICH-induced damage. These positive results in animal stroke models have encouraged the experimental study of PPAR\u03b3 in patients.\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EMaria A. Moro, PhD, Universidad Complutense, Madrid, Spain, reviewed the results of several animal studies that focused on the neuroprotective and anti-inflammatory role of PPAR\u03b3 agonists in experimental stroke models and discussed some recent clinical results involving PPAR\u03b3 ligands that have been shown to improve outcome following ischemic stroke.\u003C\/p\u003E\n         \u003Cp id=\u0022p-19\u0022\u003EUsing rats that were exposed to middle cerebral artery occlusion, administration of the PPAR\u03b3 agonists rosiglitazone, 15d PGJ(2), or L-796,449 after the ischemic onset decreased infarct volume and neuroinflammation, as well as NF\u03baB transcriptional activity [Pereira et al. \u003Cem\u003EJ Exp Neurol\u003C\/em\u003E 2005; Pereira et al. \u003Cem\u003EJ Cereb Blood Flow Metab\u003C\/em\u003E 2006].\u003C\/p\u003E\n         \u003Cp id=\u0022p-20\u0022\u003EIn addition, neuroprotective actions of PPAR\u03b3 have been shown to go beyond inflammation. A recent study has shown that GLT1\/EAAT2, the major glutamate transporter in the central nervous system, is a PPAR\u03b3 target gene. Upregulation of the expression of this transporter caused by PPAR\u03b3 activation decreases excitotoxicity and subsequent neuronal death [Romera et al. \u003Cem\u003EJ Cereb Blood Flow Metab\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-21\u0022\u003EIn a large group of stroke patients who were admitted within 24 hours of symptom onset, plasma levels of 15dPGJ(2) on admission were significantly higher than in control patients. A linear relationship between increased plasma 15-dPGJ(2) concentration and better neurological outcome at 3 months, less neurological deterioration, and smaller infarct volume was noted, indicating a neuroprotective effect for 15-dPGJ(2) in atherothrombotic ischemic stroke [Blanco M et al. \u003Cem\u003EStroke\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-22\u0022\u003EIn another clinical study, the use of PPAR\u03b3 was associated with enhanced functional recovery in stroke patients with type 2 diabetes compared with a control group [Lee J, Reding M. \u003Cem\u003ENeurochem Res\u003C\/em\u003E 2007].\u003C\/p\u003E\n         \u003Cp id=\u0022p-23\u0022\u003EDr. Moro feels that experimental evidence together with these early clinical results shows a need for larger clinical studies that use PPAR\u03b3 agonists as potential therapeutic agents not only for prevention but also for treatment of acute stroke.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2008 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/8\/1\/18.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmhep\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmhep\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}