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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemic disease is a leading cause of death and disability worldwide, and its incidence is expected to increase as the population ages. One population at particularly high risk of developing ischemia is patients with diabetes. Type 2 diabetes is associated with a marked increase in atherosclerosis, stroke and heart attack. Furthermore, the outcome following stroke and heart attack in diabetics is worse than in nondiabetic patients. In recent years, peroxisome proliferator-activated receptor (PPAR) agonists have been found to have potent antiinflammatory actions and have emerged as potential therapies for atherosclerosis and ischemia. The use of these agents is particularly attractive, since two PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), are already used chronically to treat diabetes. In this article we review the role of inflammation in ischemic disease and the biology of PPARs, and summarize the evidence that PPARgamma ligands suppress inflammation with an emphasis on atherosclerosis, and cerebral and myocardial ischemia.
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PMID:Antiinflammatory properties of PPARgamma agonists following ischemia. 1533 71

We investigated the long-term effects of the thiazolidinedione PPARgamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of malignant of hypertension. Six-week-old SHRSP were treated with pioglitazone (10 mg/kg per day p.o.) for 20 weeks. The rise in systolic blood pressure (SBP) in SHRSP was only transiently and slightly attenuated by pioglitazone (P < 0.05). On one hand, cardiac hypertrophy was little affected by the pioglitazone treatment, and there was only a reduction of subepicardial interstitial fibrosis. On the other hand, left ventricular NFkappaB and AP-1 binding activities, the expression of TNFalpha, and the adhesion of molecule PECAM were significantly decreased by pioglitazone treatment. Expression of the pro-apoptotic proteins p53 and bax was significantly increased by pioglitazone. Thus, pioglitazone-attenuated cardiac inflammation in SHRSP had little effect on BP or cardiac hypertrophy. PPARgamma activation may play a preventive cardiovascular role by offsetting the cardiac inflammatory response as demonstrated in this genetic model of malignant hypertension.
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PMID:Long-term effects of the PPAR gamma activator pioglitazone on cardiac inflammation in stroke-prone spontaneously hypertensive rats. 1564 37

Phytoestrogens are considered to be natural selective estrogen receptor modulators exerting antioxidant activity and improving vascular function. However, the mechanisms responsible for their antioxidative effects remain largely unknown. This study tested the hypothesis that genistein may provide significant endothelial protection by antioxidative effects through attenuating NADPH oxidase expression and activity. The results showed that genistein suppressed the expressions of the p22phox NADPH oxidase subunit and angiotensin II (Ang II) type 1 (AT1) receptor in a concentration- and time-dependent manner in aortic endothelial cells from stroke-prone spontaneously hypertensive rats examined by Western blot analysis. Treatment with genistein also remarkably reduced the Ang II-induced superoxide by the reduction of nitroblue tetrazolium, inhibited nitrotyrosine formation, and attenuated endothelin-1 production by ELISA via the stimulation of Ang II. However, when cells were pretreated with ICI-182780, an estrogen-receptor antagonist, at a concentration of 50 micromol/l for 30 min and then co-incubated with ICI-182780 and genistein for 24 h, the inhibitory effect of genistein was not blocked. In contrast, the inhibitory effect of genistein treatment was partially reversed by 30-min pretreatment of endothelial cells with GW9662, a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist. Genistein thus appears to act as an antioxidant at the transcription level by the downregulation of p22phox and AT1 receptor expression. Our data also showed that the PPARgamma pathway was involved, at least in part, in the inhibitory effect of genistein on the expression of p22phox and AT1 receptors. The endothelial-protective effects of phytoestrogen may contribute to improvement of cardiovascular functions.
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PMID:Genistein inhibits expressions of NADPH oxidase p22phox and angiotensin II type 1 receptor in aortic endothelial cells from stroke-prone spontaneously hypertensive rats. 1575 Feb 62

The metabolic syndrome is a worldwide epidemic, setting the stage for type 2 diabetes and its microvascular complications, and acceleration of macrovascular disease. Insulin resistance, hyperglycemia, dyslipidemia, hypertension, thrombotic disorders and adiposity define the metabolic syndrome and contribute to endothelial dysfunction and, subsequently, to accelerated atherosclerosis. Angiotensin II contributes to the development and progression of cardiovascular and renal endpoints and, as such, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate a protective effect. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR gamma), appear to impact favourably on atherosclerosis through both direct and indirect mechanisms. In humans, these ligands improve endothelial function, attenuate albuminuria and hypertension, and potentially prevent conversion of prediabetes to type 2 diabetes. Statins also have proven benefit in decreasing overall cardiovascular and stroke mortality and morbidity. The combination of angiotensin II blockade, statin therapy and PPAR gamma activation might emerge as an important global therapeutic strategy in the metabolic syndrome and diabetes. Further studies are needed to determine whether they have synergistic effects to protect the vasculature.
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PMID:Metabolic syndrome-interdependence of the cardiovascular and metabolic pathways. 1578 Aug 21

This review describes the three mammalian glutathione transferase (GST) families, namely cytosolic, mitochondrial, and microsomal GST, the latter now designated MAPEG. Besides detoxifying electrophilic xenobiotics, such as chemical carcinogens, environmental pollutants, and antitumor agents, these transferases inactivate endogenous alpha,beta-unsaturated aldehydes, quinones, epoxides, and hydroperoxides formed as secondary metabolites during oxidative stress. These enzymes are also intimately involved in the biosynthesis of leukotrienes, prostaglandins, testosterone, and progesterone, as well as the degradation of tyrosine. Among their substrates, GSTs conjugate the signaling molecules 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and 4-hydroxynonenal with glutathione, and consequently they antagonize expression of genes trans-activated by the peroxisome proliferator-activated receptor gamma (PPARgamma) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). Through metabolism of 15d-PGJ2, GST may enhance gene expression driven by nuclear factor-kappaB (NF-kappaB). Cytosolic human GST exhibit genetic polymorphisms and this variation can increase susceptibility to carcinogenesis and inflammatory disease. Polymorphisms in human MAPEG are associated with alterations in lung function and increased risk of myocardial infarction and stroke. Targeted disruption of murine genes has demonstrated that cytosolic GST isoenzymes are broadly cytoprotective, whereas MAPEG proteins have proinflammatory activities. Furthermore, knockout of mouse GSTA4 and GSTZ1 leads to overexpression of transferases in the Alpha, Mu, and Pi classes, an observation suggesting they are part of an adaptive mechanism that responds to endogenous chemical cues such as 4-hydroxynonenal and tyrosine degradation products. Consistent with this hypothesis, the promoters of cytosolic GST and MAPEG genes contain antioxidant response elements through which they are transcriptionally activated during exposure to Michael reaction acceptors and oxidative stress.
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PMID:Glutathione transferases. 1582 71

All cells, from bacterial to human, have a common, intricate response to stress that protects them from injury. Heat shock proteins (Hsps), also known as stress proteins and molecular chaperones, play a central role in protecting cellular homeostatic processes from environmental and physiologic insult by preserving the structure of normal proteins and repairing or removing damaged ones. An understanding of the interplay between Hsps and cell stress tolerance will provide new tools for treatment and drug design that maximise preservation or restoration of health. For example, the increased vulnerability of tissues to injury in some conditions, such as ageing, diabetes mellitus and menopause, or with the use of certain drugs,, such as some antihypertensive medications, is associated with an impaired Hsp response. Additionally, diseases that are associated with tissue oxidation, free radical formation, disorders of protein folding, or inflammation, may be improved therapeutically by elevated expression of Hsps. The accumulation of Hsps, whether induced physiologically, pharmacologically, genetically, or by direct administration of the proteins, is known to protect the organism from a great variety of pathological conditions, including myocardial infarction, stroke, sepsis, viral infection, trauma, neurodegenerative diseases, retinal damage, congestive heart failure, arthritis, sunburn, colitis, gastric ulcer, diabetic complications and transplanted organ failure. Conversely, lowering Hsps in cancer tissues can amplify the effectiveness of chemo- or radiotherapy. Treatments and agents that induce Hsps include hyperthermia, heavy metals (zinc and tin), salicylates, dexamethasone, cocaine, nicotine, alcohol, alpha-adrenergic agonists, PPAR-gamma agonists, bimoclomol, geldanamycin, geranylgeranylacetone and cyclopentenone prostanoids. Compounds that suppress Hsps include quercetin (a bioflavinoid), 15-deoxyspergualin (an immunosuppressive agent) and retinoic acid. Researchers who are cognisant of the Hsp-related effects of these and other agents will be able to use them to develop new therapeutic paradigms.
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PMID:Heat shock proteins: new keys to the development of cytoprotective therapies. 1599 80

Some agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) belonging to the thiazolidinedione (TZD) family, as well as the cyclopentenone prostaglandin 15-dPGJ2, have been shown to cause neuroprotection in animal models of stroke. We have tested whether the TZD-unrelated PPARgamma agonist L-796,449 is neuroprotective after permanent middle cerebral artery occlusion (MCAO) in the rat brain. Our results show that L-796,449 decreases MCAO-induced infarct size and improves neurologic scores. This protection is concomitant to inhibition of MCAO-induced brain expression of inducible NO synthase (iNOS) and the matrix metalloproteinase MMP-9 and to upregulation of the cytoprotective stress protein heme oxygenase-1 (HO-1). Analysis of the NF-kappaB p65 monomer and the NF-kappaB inhibitor IkappaBalpha protein levels as well as gel mobility shift assays indicate that L-796,449 inhibits NF-kappaB signaling, and that it may be recruiting both PPARgamma-dependent and independent pathways. In summary, our results provide new insights for stroke treatment.
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PMID:The nonthiazolidinedione PPARgamma agonist L-796,449 is neuroprotective in experimental stroke. 1614 90

Cardiovascular diseases are the leading cause of morbidity and mortality in the US. Proper management and/or prevention of atherosclerosis and hypertension, two complex and chronic disorders, would significantly reduce the risk for cardiovascular events such as myocardial infarction and stroke, but this requires an understanding of the mechanisms underlying their development and progression. Whereas a great deal has been learned and applied toward the management of these disorders, especially hypertension, morbidity and mortality remains unacceptably high, most likely because there are disease-causing mechanisms that have yet to be fully recognized. Understanding these disease mechanisms is necessary so that novel management strategies can be developed. One of these novel mechanisms centers on peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a member of the nuclear receptor superfamily of ligand-activated transcription factors known to play a role in glucose homeostasis and adipocyte differentiation and, more recently, has been shown to have anti-inflammatory, antiatherogenic, and antihypertensive effects. Thiazolidinediones, a class of drugs used in the treatment of type 2 diabetes mellitus, are high-affinity ligands for PPAR-gamma. In this review, the anti-inflammatory, anti-atherosclerotic, and anti-hypertensive mechanisms by which PPAR-gamma and its agonists are thought to exert protective effects on the cardiovascular system are discussed. Ongoing clinical trials using PPAR-gamma activators for the management of cardiovascular diseases, especially in patients with type 2 diabetes mellitus, are summarized.
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PMID:Peroxisome proliferator-activated receptor-gamma and its agonists in hypertension and atherosclerosis : mechanisms and clinical implications. 1625 27

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: alpha, beta (sometimes called delta), and gamma. The better studied are PPARalpha and PPARgamma, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARbeta and that its selective activation inhibits platelet aggregation. PPARbeta is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARbeta ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARbeta is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARbeta as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.
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PMID:Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARbeta. 1636 17

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.
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PMID:Pioglitazone: an antidiabetic drug with the potency to reduce cardiovascular mortality. 1650 18


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