Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the discovery of vitamin E in 1922, its deficiency has been associated with various disorders, particularly atherosclerosis, ischemic heart disease, and the development of different types of cancer. A neurological syndrome associated with vitamin E deficiency resembling Friedreich ataxia has also been described. Whereas epidemiological studies have indicated the role of vitamin E in preventing the progression of atherosclerosis and cancer, intervention trials have produced contradictory results, indicating strong protection in some cases and no significant effect in others. Although it is commonly believed that phenolic compounds like vitamin E exert only a protective role against free radical damage, antioxidant molecules can exert other biological functions. For instance, the antioxidant activity of 17-beta-estradiol is not related to its role in determining secondary sexual characters, and the antioxidant capacity of all-trans-retinal is distinguished from its role in rhodopsin and vision. Thus, it is not unusual that alpha-tocopherol (the most active form of vitamin E) has properties independent of its antioxidant/radical scavenging ability. The Roman god Janus, shown in ancient coins as having two faces in one body, inspired the designation of 'Janus molecules' for these substances. The new biochemical face of vitamin E was first described in 1991, with an inhibitory effect on cell proliferation and protein kinase C activity. After a decade, this nonantioxidant role of vitamin E is well established, as confirmed by authoritative studies of signal transduction and gene regulation. More recently, a tocopherol binding protein with possible receptor function has been discovered. Despite such important developments in understanding the molecular mechanism and the targets of vitamin E, its new Janus face is not fully elucidated. Greater knowledge of the molecular events related to vitamin E will help in selecting the parameters for clinical intervention studies such as population type, dose response effects, and possible synergism with other compounds.
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PMID:Vitamin E: protective role of a Janus molecule. 1168 57

Vascular endothelial growth factor (VEGF) is an angiogenic mitogen, specific for endothelial cells. Hypoxia-induced VEGF in endothelial cells and cardiomyocytes leads to autocrine and paracrine stimulation, respectively. During myocardial ischemia, VEGF is upregulated in the endothelium and myocardium, and may mediate angiogenesis. Morphine sulfate is commonly used in pain relief for patients with acute myocardial infarction. We investigated the effect of morphine sulfate on VEGF expression in cultured endothelial cells and cardiac myocytes subjected to hypoxia. Enzyme-linked immunosorbent assays showed that morphine sulfate significantly inhibited hypoxia-induced VEGF expression in mouse heart microvascular endothelial cells (SMHEC4), primary cultures of human umbilical vein endothelial cells (HUVECs) and in primary cultures of rat cardiac myocytes (P<0.05). Real time reverse transcriptase polymerase chain reaction showed that morphine treatment (100 ng/ml) of hypoxic HUVECs resulted in a significant reduction in mRNA levels of VEGF(121) and VEGF(165) isoforms. Transfection of HUVECs with a human VEGF promoter-luciferase construct showed that hypoxia-induced transcriptional activation of VEGF was markedly inhibited by morphine sulfate (P<0.05). Phosphatidyl inositol-3 kinase and protein kinase C-mediated activation of the VEGF promoter was also inhibited by morphine. The opioid antagonist naloxone significantly reversed the inhibitory effects of morphine in endothelial cells suggesting the involvement of opioid receptors. Our results show that the inhibitory effects of morphine on hypoxia-induced VEGF expression in endothelial cells and cardiac myocytes can lead to a decrease in the autocrine and paracrine stimulation and hence limit neovascularization of the ischemic myocardium.
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PMID:Morphine sulfate inhibits hypoxia-induced vascular endothelial growth factor expression in endothelial cells and cardiac myocytes. 1173 63

We have cloned a prostacyclin (PGI2) stimulating factor (PSF), which stimulates PGI2 production by vascular endothelial cells. Previous study demonstrated the reduced PSF expression in the coronary arteries from the patients with ischemic heart disease. To clarify the mechanism of reduced PSF expression in atherosclerosis, we examined the effect of lysophosphatidylcholine (lysoPC), a main component of oxidized low density lipoprotein (LDL), on PSF expression in cultured vascular smooth muscle cells. LysoPC reduced PSF expression dose-dependently. Whereas neither phosphatidylcholine nor native LDL affects the PSF expression. Calphostin C, a protein kinase C (PKC) inhibitor, restored the reduction of PSF expression by lysoPC. These results suggest that lysoPC-induced reduction of PSF expression is mediated by PKC activation and is playing a role in the initiation and progression of atherosclerotic lesions.
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PMID:Lysophosphatidylcholine inhibits the expression of prostacyclin stimulating factor in cultured vascular smooth muscle cells. 1187 73

Recent evidence supports a beneficial effect of testosterone on the cardiovascular system. Testosterone acts as a coronary vasodilator and reduces myocardial ischemia in men with coronary heart disease. The aim of the current study was to determine whether testosterone has a similar vasodilatory action in the pulmonary circulation and to characterize the underlying mechanism of action. The vasodilatory action of testosterone was studied in pulmonary arteries (n = 132, mean internal diameter = 344 +/- 8 microm) isolated from male rats (n = 48, mass = 396 +/- 7 g) mounted in a small vessel wire myograph and loaded to a tension equivalent to 17.5 mm Hg. Micromolar concentrations of testosterone induced dilatation in pulmonary arteries preconstricted with prostaglandin F2alpha (100 microM) within seconds of application. Dilatation to testosterone was similar in vessels treated with N-gamma-nitro-l-arginine methyl ester (l-NAME) (10 microM) or vehicle (5 microl distilled water), -38.2 +/- 2.9%, and -38.1 +/- 3.4%, respectively, and in vessels treated with indomethacin (10 microM), flutamide (10 microM), or vehicle (5 microl ethanol), -35.5 +/- 2.8%, -43.2 +/- 3.6%, and -35.7 +/- 4.6%, respectively (all p > 0.05). Maximal dilatation to testosterone occurred following preconstriction with agents that activated voltage-gated calcium channels such as prostaglandin F2alpha (-34.6 +/- 5.0%), BAY K8644 (-32.9 +/- 8.7), or potassium chloride (-26.7 +/- 1.5%), compared with calcium-independent protein kinase C activation by phorbol dibutyrate (-14.7 +/- 1.6%) or capacitative calcium entry via thapsigargin (-5.1 +/- 0.9%). This study demonstrates that testosterone induces pulmonary dilatation via a mechanism that is independent of the classic androgen receptor and also of the release of nitric oxide or dilator prostaglandins. The data support a calcium antagonistic action for testosterone in the pulmonary circulation, primarily against voltage-gated calcium channels.
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PMID:Pulmonary vasodilatory action of testosterone: evidence of a calcium antagonistic action. 1202 75

Necrosis and apoptosis are two forms of cell death in the myocardium that have been associated with ischemia and reperfusion. Although it has been well documented that necrosis, as a major form of myocyte cell death, rapidly leads to a destruction of a large group of cells after myocardial ischemia and reperfusion, the induction of apoptosis in myocardium, primarily triggered during reperfusion, may independently contribute to the extension of cell death (i.e. infarction) in a dynamic manner. Ischemic preconditioning (IP), an endogenous protective mechanism rapidly evoked by a brief period of ischemia, is recognized for its protection in limiting myocardial necrosis, but has also shown a profound inhibition in apoptosis. While much research has been done on the reduction of necrosis by IP, there remains no clear understanding of the time course of inhibition of apoptosis by IP after long-term reperfusion. In this review, we will show the time course of necrosis and apoptosis during reperfusion, focus on the role of apoptosis in the extension of lethal myocyte injury, and summarize the potential mechanisms involved in reducing apoptosis by IP. 'Classic' or 'early' IP has been shown to reduce apoptosis in part by inhibiting inflammatory cell activation and altering the expression of anti- and pro-apoptotic proteins as well as protein kinase C activity. It remains unknown, however, whether delayed IP participates in the attenuation of apoptosis in addition to necrosis. The demonstration of a 'window of opportunity' in inhibiting apoptosis by IP will provide new directions in research investigating mechanisms underlying myocyte cell death during reperfusion, and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.
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PMID:Myocardial apoptosis and ischemic preconditioning. 1216 Sep 41

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR protein and activity and in the myocardial content of sorbitol, a unique product of AR catalysis. Pretreatment with N(omega)-nitro-L-arginine, a nitric oxide synthase inhibitor, or chelerythrine, a protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR protein 24 hours later, demonstrating that ischemic PC upregulates AR via nitric oxide- and protein kinase C-dependent signaling pathways. The AR-selective inhibitors tolrestat and sorbinil prevented AR-mediated accumulation of sorbitol and abrogated the infarct-sparing effect of late PC, demonstrating that enhanced AR activity is necessary for this cardioprotective phenomenon to occur. Inhibition of AR did not affect infarct size or the myocardial accumulation of the lipid peroxidation product 4-hydroxy trans-2-nonenal (HNE) in nonpreconditioned rabbits. The accumulation of HNE was inhibited by late PC, and this effect was abrogated by sorbinil. Taken together, these results establish AR as an essential mediator of late PC. Furthermore, the data suggest that myocardial ischemia/reperfusion injury is due in part to the generation of lipid peroxidation products and that late PC diminishes this source of injury by upregulating AR.
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PMID:Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. 1216 50

To delineate the in vivo cardiac functions requiring normal delta protein kinase C (PKC) activity, we pursued loss-of-function through transgenic expression of a deltaPKC-specific translocation inhibitor protein fragment, deltaV1, in mouse hearts. Initial results using the mouse alpha-myosin heavy chain (alphaMHC) promoter resulted in a lethal heart failure phenotype. Viable deltaV1 mice were therefore obtained using novel attenuated mutant alphaMHC promoters lacking one or the other thyroid response element (TRE-1 and -2). In transgenic mouse hearts, deltaV1 decorated cytoskeletal elements and inhibited ischemia-induced deltaPKC translocation. At high levels, deltaV1 expression was uniformly lethal, with depressed cardiac contractile function, increased expression of fetal cardiac genes, and formation of intracardiomyocyte protein aggregates. Ultrastructural and immunoconfocal analyses of these aggregates revealed focal cytoskeletal disruptions and localized concentrations of desmin and alphaB-crystallin. In individual cardiomyocytes, cytoskeletal abnormalities correlated with impaired contractile function. Whereas desmin and alphaB-crystallin protein were increased approximately 4-fold in deltaV1 hearts, combined overexpression of these proteins at these levels was not sufficient to cause any detectable cardiac pathology. At low levels, deltaV1 expression conferred striking resistance to postischemic dysfunction, with no measurable effects on basal cardiac structure, function, or gene expression. Intermediate expression of deltaV1 conferred modest basal contractile depression with less ischemic protection, associated with abnormal cardiac gene expression, and a histological picture of infrequent cardiomyocyte cytoskeletal deformities. These results validate an approach of deltaPKC inhibition to protect against myocardial ischemia, but indicate that there is a threshold level of deltaPKC activation that is necessary to maintain normal cardiomyocyte cytoskeletal integrity.
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PMID:Ischemic protection and myofibrillar cardiomyopathy: dose-dependent effects of in vivo deltaPKC inhibition. 1238 52

Apolipoprotein AI (apo AI) is the major protein component of serum high-density lipoproteins. The abundance of apo AI correlates inversely with the risk of ischemic heart disease (IHD) and thus enhanced expression of the protein is expected to reduce the risk of IHD. Our previous studies show that insulin enhances apo AI promoter activity and this action requires the GC-rich insulin response core element (IRCE, -411 to -404). The motif binds to a ubiquitous transcription factor Sp1. We have extended studies that examine insulin induction of apo AI using a 41 bp (-425 to -385) fragment of apo AI DNA linked to the trout metallothionein TATA box and fused to luciferase (pIRCE-Luc). Luc activity in Hep G2 cells transfected with pIRCE-Luc was stimulated by insulin, an insulin mimetic bisperoxo (1,10-phenanthroline) oxovanadate (bpv) and the phorbol ester (PDBu). Our previous studies showed that insulin action on apo AI gene transcription flowed down two signaling pathways: Ras-raf and PI3K, leading to activation of the MAPK and PKC kinases, respectively. In contrast, PDBu activates only the PKC pathway. Although insulin and PDBu activation of apo AI were distinct, the cascades involved all appeared to target Sp1. Furthermore, exposure of transfected cells to okadaic acid or a phosphatase inhibitor also increased Luc activity and suggested a potential role for phosphorylation, likely involving Sp1. If true, then changes in the IRCE binding activity of Sp1 should be detected following exposure to MAPK, PKC, or the protein phosphatase I (PPI) alone and in various combinations followed by assaying the ability of Sp1 to bind the IRCE. Sp1 binding activity increased with either MAPK or PKC. Although exposure to PPI also affected IRCE binding activity of Sp1, whether it increased or decreased was dependent on the order of exposure to the protein. In summary, the IRCE alone can mediate the stimulatory effects of insulin, bpv, and PDBu, and Sp1 enhances these responses that may arise from phosphorylation of the protein.
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PMID:Insulin induction of apolipoprotein AI, role of Sp1. 1261 63

Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4',6'-diamidine-2'-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ETA receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-xL, an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-xL, and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-xL expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ETA receptor and the subsequent c-Src/Bcl-xL-dependent pathway.
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PMID:Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. 1266 84

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.
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PMID:Signal transduction and Ca2+ signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium. 1269 35


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