Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.
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PMID:Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. 875 16

Hypoxia-inducible factor 1 (HIF-1) is a basic-helix-loop-helix transcription factor that plays essential roles in mammalian development and physiology. HIF-1 is a heterodimer composed of HIF-1alpha and HIF-1beta subunits. The expression and activity of the HIF-1alpha subunit are tightly regulated by cellular O2 concentration. Under hypoxic conditions, HIF-1 activates the transcription of genes encoding erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase O2 delivery or facilitate metabolic adaptation to hypoxia. HIF-1 is essential for embryonic vascularization and survival, neovascularization in ischemic myocardium, hypoxia-induced pulmonary vascular remodeling, and tumor vascularization. HIF-1alpha is overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. Pharmacologic manipulation of HIF-1 levels may provide a novel therapeutic approach to diseases that represent the most common causes of mortality in Western society, including cancer, chronic lung disease, and myocardial ischemia.
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PMID:Expression of hypoxia-inducible factor 1: mechanisms and consequences. 1060 34

Endothelin-1 (Et-1) is a vasoconstrictor peptide that plays an important role in the pathophysiology of hypertension, myocardial ischemia, and other diseases. We examined the mechanism of regulation the Et-1 mRNA expression in human microvascular endothelial cells (HMEC-1) in response to hypoxia and cobalt. To determine whether the 5'-flanking region of Et-1 gene mediate transcriptional responses to cellular hypoxia, we constructed reporter plasmids in which Et-1 5'-flanking sequences of Et-1 gene were fused to luciferase coding sequences. Constructs, which contain native Et-1 sequence 5'-AACGTGCA-3', located between -118 and -125 in the opposite orientation as the transcriptional unit, mediate transcriptional response to hypoxia and cobalt. This responsiveness was inhibited by genistein, a tyrosine kinase selective inhibitor. Both hypoxia and cobalt induced binding of HIF-1 (hypoxia inducible-1 factor) to this Et-1 hypoxia responsive element in gel shift assays. Mutation in this sequence eliminated both the hypoxia-induced HIF-1 binding and luciferase expression. Using the supershift assay we have shown that this hypoxia responsive element binds HIF-1alpha and HIF-1beta proteins. Interestingly, genistein only slightly affected HIF-1 binding. These results indicate that the Et-1 gene contains HIF-1 binding hypoxia responsive elements which mediate transcriptional responses to hypoxia and cobalt in microvascular endothelial cells. Genistein appears to inhibit this response by affecting the transcriptional activity of the HIF-1 complex, without significantly affecting its DNA-binding properties.
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PMID:Regulation of endothelin-1 gene expression in human microvascular endothelial cells by hypoxia and cobalt: role of hypoxia responsive element. 1093 28

Endothelin-1 (ET-1) is a peptide hormone with potent vasoconstrictor properties which is synthesized and secreted predominantly by vascular endothelial cells. Its production is regulated by numerous stimuli including ischemia and hypoxia, and the enhanced levels that occur during myocardial ischemia may contribute to the progression of heart failure. We reported previously a preliminary characterization of a hypoxia-inducible factor-1 (HIF-1) binding site in the human ET-1 promoter which contributed to the activation of ET-1 expression in endothelial cells. We report here that the HIF-1 binding site alone is not sufficient for the response to hypoxia but requires an additional 50 base pairs of flanking sequence that includes binding sites for the factors activator protein-1 (AP-1), GATA-2, and CAAT-binding factor (NF-1). Mutation of any one of these sites or the HIF-1 site eliminated induction by hypoxia. Mutations of the AP-1 and GATA-2 sites, but not the HIF-1 site, were complemented by overexpressing AP-1, GATA-2, HIF-1alpha, or the activator protein p300/CBP, restoring the response to hypoxia. Binding studies in vitro confirmed physical associations among GATA-2, AP-1, and HIF-1 factors. Overexpression or depletion of p300/CBP modulated the level of ET-1 promoter expression as well as the endogenous ET-1 transcript but did not change the fold induction by hypoxia in either case. Regulation of the ET-1 promoter by hypoxia in non-endothelial cells required overexpression of GATA-2 and HIF-1alpha. The results support essential roles for AP-1, GATA-2, and NF-1 in stabilizing the binding of HIF-1 and promoting recruitment of p300/CBP to the ET-1 hypoxia response complex.
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PMID:Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. 1127 91

Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1alpha is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1alpha and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O(2)(-)) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1alpha and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O(2)(-) (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O(2)(-), and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia.
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PMID:Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. 1533 49

Electrical stimulation of the vagal efferent nerve improves the survival of myocardial infarcted rats. However, the mechanism for this beneficial effect is unclear. We investigated the effect of acetylcholine (ACh) on hypoxia-inducible factor (HIF)-1alpha using rat cardiomyocytes under normoxia and hypoxia. ACh posttranslationally regulated HIF-1alpha and increased its protein level under normoxia. ACh increased Akt phosphorylation, and wortmannin or atropine blocked this effect. Hypoxia-induced caspase-3 activation and mitochondrial membrane potential collapse were prevented by ACh. Dominant-negative HIF-1alpha inhibited the cell protective effect of ACh. In acute myocardial ischemia, vagal nerve stimulation increased HIF-1alpha expression and reduced the infarct size. These results suggest that ACh and vagal stimulation protect cardiomyocytes through the PI3K/Akt/HIF-1alpha pathway.
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PMID:Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1alpha. 1581 27

BNP (brain-type natriuretic peptide) is a cardiac hormone with systemic haemodynamic effects as well as local cytoprotective and antiproliferative properties. It is induced under a variety of pathophysiological conditions, including decompensated heart failure and myocardial infarction. Since regional hypoxia is a potential common denominator of increased wall stretch and myocardial hypoperfusion, we investigated the direct effects of hypoxia on BNP expression, and the role of the HIF (hypoxia-inducible transcription factor) in BNP regulation. Using an RNase protection assay we found a strong hypoxic induction of BNP mRNA expression in different cell lines and in cultured adult rat cardiomyocytes. Systemic hypoxia and exposure to 0.1% CO induced BNP expression in the rodent myocardium in vivo, although this was at a lower amplitude. BNP promoter-driven luciferase expression increased 10-fold after hypoxic stimulation in transient transfections. Inactivation of four putative HREs (hypoxia-response elements) in the promoter by site-directed mutagenesis revealed that the HRE at -466 nt was responsible for hypoxic promoter activation. A functional CACAG motif was identified upstream of this HRE. The HIF-1 complex bound specifically and inducibly only to the HRE at -466 nt, as shown by EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). siRNA (small interfering RNA)-mediated knockdown of HIF-1alpha, but not HIF-2alpha, interfered with hypoxic BNP mRNA induction and BNP promoter activation, confirming that BNP is a specific HIF-1alpha target gene. In conclusion, BNP appears to be part of the protective program steered by HIF-1 in response to oxygen deprivation. Induction of BNP may therefore contribute to the potential benefits of pharmacological HIF inducers in the treatment of ischaemic heart disease and heart failure.
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PMID:Hypoxia, via stabilization of the hypoxia-inducible factor HIF-1alpha, is a direct and sufficient stimulus for brain-type natriuretic peptide induction. 1782 84

Hypoxia-inducible transcription factor 1 (HIF-1) and HIF-2alpha regulate the expression of an expansive array of genes associated with cellular responses to hypoxia. Although HIF-regulated genes mediate crucial beneficial short-term biological adaptations, we hypothesized that chronic activation of the HIF pathway in cardiac muscle, as occurs in advanced ischemic heart disease, is detrimental. We generated mice with cardiac myocyte-specific deletion of the von Hippel-Lindau protein (VHL), an essential component of an E3 ubiquitin ligase responsible for suppressing HIF levels during normoxia. These mice were born at expected frequency and thrived until after 3 months postbirth, when they developed severe progressive heart failure and premature death. VHL-null hearts developed lipid accumulation, myofibril rarefaction, altered nuclear morphology, myocyte loss, and fibrosis, features seen for various forms of human heart failure. Further, nearly 50% of VHL(-/-) hearts developed malignant cardiac tumors with features of rhabdomyosarcoma and the capacity to metastasize. As compelling evidence for the mechanistic contribution of HIF-1alpha, the concomitant deletion of VHL and HIF-1alpha in the heart prevented this phenotype and restored normal longevity. These findings strongly suggest that chronic activation of the HIF pathway in ischemic hearts is maladaptive and contributes to cardiac degeneration and progression to heart failure.
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PMID:Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. 1828 56

Hypoxia-inducible factor (HIF)-1alpha and-2alpha have diverse actions on the myocardium, but the importance of direct effects on cardiac myocytes is unclear. To define their regional accumulation and association with cardiomyocyte cell cycle change after myocardial infarction (MI), a rat MI model was established by occluding the coronary arteries. To further prove a causative relationship between HIF and cell cycle regulation, cultured cardiomyocytes were transfected with adenoviral vectors carrying HIF-1alpha and HIF-2alpha. Two weeks after MI, both HIF-1alpha and HIF-2alpha mRNA were moderately increased in the infarcted left ventricle and noninfarcted left ventricle; HIF-2alpha amplification was also detected in areas of the interventricular septum and the right ventricle. In concordance with the changes in mRNA levels, immunohistochemistry signals of HIF-1alpha and HIF-2alpha were characterized by different regional distributions. In the myocardium adjacent to the infarcted tissue, a significant correlation between HIF-1alpha or HIF-2alpha and Ki-67 labeling index was observed (P < 0.001). Immunohistochemical double staining showed that HIF positive cardiomyocytes underwent DNA synthesis. Cardiomyocytes treated with HIF-1alpha or -2alpha expressed Ki-67, phosphohistone H3, and bromodeoxyuridine effectively in vitro. In conclusion, HIF-1alpha and HIF-2alpha had a distinct spatial expression pattern in a rat model of ischemic heart disease. Both HIF subunits might be potent stimuli for cardiomyocytes to re-enter the cell cycle and initiate DNA synthesis.
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PMID:Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats. 1848 63

The hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure. The HIF system was characterized in left ventricular myocardia from 18 explanted failing hearts and 11 non-failing donor hearts by quantitative RT-PCR and Western analysis. HIF-1alpha mRNA levels were significantly decreased while its natural antisense transcript aHIF was nearly twofold higher (p<0.01) in failing myocardia than in control hearts. Moreover, compared to donor hearts a significantly increased expression of HIF-3alpha, which may act as a competitive inhibitor of HIF-1/2alpha activity, and PHD3, which upon hydroxylation of prolyl residues directs HIF-alpha subunits towards proteasomal degradation, was observed in the failing myocardium. Although negative regulators of HIF were induced, the HIF pathway obviously remains activated in chronic human heart failure, because prototype HIF target genes, such as ABCG2, VEGF, and BNIP3, were significantly induced.
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PMID:Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human end-stage heart failure. 1878 60


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