UMLS:C0151744 - FACTA Search

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Query: UMLS:C0151744 (myocardial ischemia)
31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
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PMID:Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. 1208 64

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

Peroxisome proliferator-activated receptor (PPAR)-gamma modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-gamma activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-gamma activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both alpha-tocopherol and thiazolidinedione moieties, whether PPAR-gamma activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg x kg(-1) x day(-1)), rosiglitazone (3 mg x kg(-1) x day(-1)), or alpha-tocopherol (73 mg x kg(-1) x day(-1), equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-gamma, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or alpha-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an alpha-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-gamma activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its alpha-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-gamma activation in the heart.
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PMID:PPAR-gamma activation fails to provide myocardial protection in ischemia and reperfusion in pigs. 1552 32

Ischemic preconditioning, the most powerful protection against infarction, activates PI3Kinase (PI3K)/AKT and P42/44MAPK. Pioglitazone, a thiazolidinedione and PPARgamma receptor agonist used in Type II diabetes treatment, has been shown to activate these kinase cascades. We therefore hypothesized that pioglitazone could protect the myocardium when given prior to myocardial ischemia/reperfusion injury. Langendorff perfused rat hearts underwent 40 minutes of stabilization then 35 minutes of regional ischemia and 120 minutes of reperfusion (control) or Pioglitazone (1, 2, 5, and 10 microM)-given before ischemia. Additional groups underwent the same protocol but with either PI3K inhibitors (15 microM LY294002 or 100 nM wortmannin) or P42/44MAPK inhibitors (10 microM U0126 or 10 microM PD98059) given either during stabilization or at reperfusion. Infarct size was determined as a percentage of risk zone (I/R%). Pioglitazone (2 microM) significantly reduced I/R% compared with control (25.4 +/- 3.1 versus 47.3 +/- 3.4; P < 0.05). This protection was abolished by PI3K inhibitors (pioglitazone+LY294002 46.5 +/- 5.0, pioglitazone + wortmannin 48.8 +/- 4.6 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) but not by P42/44MAPK inhibitors (pioglitazone+U0126 30.7 +/- 5.7, pioglitazone + PD98059 28.5 +/- 6.3 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05) given in stabilization. However when the inhibitors were given at reperfusion, the protection was abrogated by blocking either pathway (pioglitazone+LY294002 49.8 +/- 3.1, pioglitazone+U0126 48.7 +/- 3.7 versus pioglitazone alone 25.4 +/- 3.1; P < or = 0.05). In conclusion pioglitazone induced significant protection against ischemia/reperfusion injury when administered prior to ischemia. This protection appears to involve PI3K and P42/44MAPK.
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PMID:Pioglitazone mimics preconditioning in the isolated perfused rat heart: a role for the prosurvival kinases PI3K and P42/44MAPK. 1630 7

Two hypotheses explain the role of adult progenitor cells in myocardial regeneration. Stem cell plasticity which involves mobilization of stem cells from the bone marrow and other niches, homing to the area of tissue injury and transdifferentiation into functional cardiomyocytes. Alternative hypothesis is based on the observations that bone marrow harbors a heterogenous population of cells positive for CXCR4 - receptor for chemokine SDF-1. This population of non-hematopoietic cells expresses genes specific for early muscle, myocardial and endothelial progenitor cells (EPC). These tissue-committed stem cells circulate in the peripheral blood at low numbers and can be mobilized by hematopoietic cytokines in the setting of myocardial ischemia. Endothelial precursors capable of transforming into mature, functional endothelial cells are present in the pool of peripheral mononuclear cells in circulation. Their number significantly increases in acute myocardial infarction (AMI) with subsequent decrease after 1 month, as well as in patients with unstable angina in comparison to stable coronary heart disease (CHD). There are numerous physiological and pathological stimuli which influence the number of circulating EPC such as regular physical activity, medications (statins, PPAR-gamma agonists, estrogens), as well as numerous inflammatory and hematopoietic cytokines. Mobilization of stem cells in AMI involves not only the endothelial progenitors but also hematopoietic, non-hematopoietic stem cells and most probably the mesenchymal cells. In healthy subjects and patients with stable CHD, small number of circulating CD34+, CXCR4+, CD117+, c-met+ and CD34/CD117+ stem cells can be detected. In patients with AMI, a significant increase in CD34+/CXCR4+, CD117+, c-met+ and CD34/CD117+ stem cell number the in peripheral blood was demonstrated with parallel increase in mRNA expression for early cardiac, muscle and endothelial markers in peripheral blood mononuclear cells. The maximum number of stem cells was found early in ST-segment elevation myocardial infarction (<12 hours) with subsequent decrease through the 7-day follow-up and with concomitant changes in the levels of cytokines involved in the inflammatory response and stem cell recruitment. Moreover, peak expression of cardiac muscle and endothelial markers occurred at the same time as the most significant increase in CD34/CXCR4+ stem cell number. The SDF-1/CXCR-4 axis seems particularly important in stem/muscle progenitor cell homing, chemotaxis, engraftment and retention in ischaemic myocardium. The significance of autologous stem cells mobilization in terms of cardiac salvage and regeneration needs to be proved in humans but it seems to be a reparative mechanism triggered early in the course of acute coronary syndromes.
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PMID:Mobilization of bone marrow-derived progenitor cells in acute coronary syndromes. 1638 90

In this study, experiments were designed to determine if peroxisome proliferator-activated receptor (PPAR) alpha agonists could decrease myocardial ischemia/reperfusion injury after cardioplegia-induced cardiac arrest under cardiopulmonary bypass, attenuate the appearance of cardiomyocytic apoptosis, and decrease the damage of reactive oxygen species. Cardiomyocytic apoptosis occurs after cardiopulmonary bypass surgery. Reactive oxygen species and peroxynitrite generated during ischemia/reperfusion initiate the formation of single-strand DNA breaks. Peroxisome proliferator-activated receptors (PPARs) activators had an important role in alleviating myocardial apoptosis. Four groups of New Zealand white rabbits (10 in each group, each 2.5-3.5 kg) underwent cardiopulmonary bypass. Thirty minutes before surgery, one group received WY14643 (a PPAR-alpha agonist, 1 mg kg(-1)) and another received 15D-PGJ2 (a PPAR-gamma agonist; 0.3 mg kg(-1)). The ascending aorta was cross-clamped for 60 min, whereas intermittent cold crystalloid cardioplegic solution was infused into the aortic root every 20 min. The myocardium of the reperfused hearts and control hearts were harvested and studied in vitro for evidence of apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling method and Western blot analyses of cytochrome c and apoptosis-inducing factor. The reactive oxidative insults were checked using enzyme-linked immunosorbent assay to detect plasma cytokine levels. The occurrence of cardiomyocytic apoptosis and elevation of plasma cytokines were significantly lower in the group receiving PPAR-alpha agonists than in the other groups. Western blot analysis of apoptosis-inducing factor and cytochrome c revealed similar patterns. PPAR-alpha activation could diminish postischemic cardiomyocytic apoptosis and reactive oxygen species injuries after global cardiac arrest under cardiopulmonary bypass, possibly via prevention of both caspase-dependent and caspase-independent apoptotic pathways.
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PMID:Cardiomyocytic apoptosis following global cardiac ischemia and reperfusion can be attenuated by peroxisome proliferator-activated receptor alpha but not gamma activators. 1691 51

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that regulates diverse biological functions including inflammation. The PPARgamma ligands have been reported to exert cardioprotective effects and attenuate myocardial reperfusion injury. Here, we examined the molecular mechanisms of their anti-inflammatory effects. Male Wistar rats were subjected to myocardial ischemia and reperfusion and were treated with the PPAR-gamma ligands, 15-deoxy-Delta-prostaglandin J2 (15d-PGJ2) or ciglitazone, or with vehicle only, in the absence or presence of the selective PPAR-gamma antagonist GW-9662. In vehicle-treated rats, myocardial injury was associated with elevated tissue activity of myeloperoxidase, indicating infiltration of neutrophils, and elevated plasma levels of creatine kinase and tumor necrosis factor-alpha. These events were preceded by activation of the nuclear factor-kappaB pathway. The PPAR-gamma DNA binding was also increased in the heart after reperfusion. Treatment with ciglitazone or 15d-PGJ2 reduced myocardial damage and neutrophil infiltration and blunted creatine kinase levels and cytokine production. The beneficial effects of both ligands were associated with enhancement of PPAR-gamma DNA binding and reduction of nuclear factor-kappaB activation. Treatment with 15d-PGJ2, but not ciglitazone, enhanced DNA binding of heat shock factor 1 and upregulated the expression of the cardioprotective heat shock protein 70. Treatment with 15d-PGJ2, but not ciglitazone, also induced a significant increase in nuclear phosphorylation of the prosurvival kinase Akt. The cardioprotection afforded by ciglitazone was attenuated by the PPAR-gamma antagonist GW-9662. In contrast, GW-9662 did not affect the beneficial effects afforded by 15d-PGJ2. Thus, our data suggest that treatment with these chemically unrelated PPAR-gamma ligands results in diverse anti-inflammatory mechanisms.
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PMID:Diverse cardioprotective signaling mechanisms of peroxisome proliferator-activated receptor-gamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone, in reperfusion injury: role of nuclear factor-kappaB, heat shock factor 1, and Akt. 1758 86

Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice. Acetylcholine (ACh), adenosine-5'-diphosphate (ADP), NaF, a G protein activator and A-23187, a Ca-ionophore, caused endothelium-dependent and nitric oxide (NO)-mediated relaxation, and sodium nitroprusside (SNP), an NO donor, caused endothelium-independent relaxation in the pre-contracted aorta of db/db mice. Maximal endothelium-dependent ACh-induced relaxation was reduced in diabetic but not pre-diabetic db/db mice compared to age-matched db/+ mice, while maximal SNP-induced relaxation was not different between diabetic and non-diabetic mice. ACh-induced relaxation in diabetic db/db mice was not affected by ozagrel, a thromboxane A2 (TXA2) synthetase inhibitor, or acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor, suggesting no involvement of endogenous TXA2 or prostanoids in the reduction of relaxation. Maximal endothelium-dependent ADP-, A-23187-, and NaF-induced relaxation was not reduced in diabetic db/db mice. EC50 values for ACh- and SNP-induced relaxation were increased in diabetic but not pre-diabetic db/db mice, suggesting decreases in sensitivity to NO in diabetic mice. Two-week treatment with KV-5070, a PPARgamma agonist, lowered plasma glucose, triglyceride (TG), and insulin but not cholesterol, and reversed the reduced ACh-induced relaxation. In conclusion, ACh-induced endothelium-dependent relaxation is impaired in diabetic db/db mice, probably due to the dysfunction of ACh receptors and/or receptor-G protein coupling. Endothelial dysfunction was not genetic and was considered to be initiated primarily by hyperglycemia, and was improved by anti-diabetic treatment with a PPARgamma agonist.
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PMID:Impairment of endothelium-dependent ACh-induced relaxation in aorta of diabetic db/db mice--possible dysfunction of receptor and/or receptor-G protein coupling. 1822 1

The present study was undertaken to examine the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, using different administration methods, on rat myocardial infarct size induced by 30 min of ischemia followed by 4 h of reperfusion. The infarct size was significantly reduced by the continuous infusion of rosiglitazone (0.5 mg/kg/h) from 30 min before occlusion for 2 h. On the other hand, limitation of the infarct size was shown by a bolus injection of 0.75 mg/kg at 5 min before reperfusion, but not by a bolus injection of 1 mg at 30 min before occlusion. The protective effect of rosiglitazone by the bolus injection before occlusion was obtained when an antioxidant, N-acetylcysteine, was concomitantly administered. The cardioprotection by rosiglitazone was associated with the inhibition of increased myeloperoxidase activity, tumor necrosis factor-alpha content and phosphorylation of inhibitor kappaB in the myocardium. The present study demonstrated that the protective effect of rosiglitazone on myocardial ischemia/reperfusion injury occurred most likely by inhibition of the nuclear factor-kappaB pathway through PPAR-gamma activation. However, acute treatment with rosiglitazone is harmful if its concentration is high during ischemia.
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PMID:Different effect of acute treatment with rosiglitazone on rat myocardial ischemia/reperfusion injury by administration method. 1857 44

Pioglitazone is a widely used anti-type 2 diabetic drug. Beside its insulin-sensitizing effects, pioglitazone exerts preventive roles against ischemic heart disease. Since one possible explanation is anti-hypertensive action, we examined effects of pioglitazone on contractility of isolated blood vessel. Endothelium-intact [End (+)] or -removed [End (-)] rat aorta is isolated and isometric tension is recorded. In both End (+) and End (-) aorta, pretreatment with pioglitazone (3 - 10 microM, 30 min) inhibited noradrenaline (NA) (1 nM - 1 microM)-induced contraction. In NA (100 nM)-pre-contracted aorta, pioglitazone (1 - 10 microM) directly induced a relaxation. The relaxant effect is higher in End (-) aorta than in End (+) aorta. In End (+) aorta, N(G)-nitro-L-arginine methyl ester (100 microM) significantly inhibited the relaxation. In End (-) aorta, neither indomethacin nor cimetidine affected the relaxation, but tetraethylammonium (10 mM) inhibited it. Furthermore, the relaxation was significantly inhibited by a voltage-dependent K+ (K(V))-channel blocker, 4-aminopyridine (1 mM), or an inward rectifying K+ (K(IR))-channel blocker, BaCl2 (1 mM). GW9662 (2 microM), a blocker of peroxisome proliferator-activated receptor (PPAR)-gamma was ineffective against the relaxation. The present study demonstrated that pioglitazone causes PPAR-gamma-independent relaxation. While endothelium-dependent relaxation is mediated via nitric oxide, the endothelium-independent one is responsible for smooth muscle K+ (K(V), K(IR))-channel opening.
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PMID:Mechanisms underlying pioglitazone-mediated relaxation in isolated blood vessel. 1898 33

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