Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of the retina is sensitive to oxygen tension. Any change in the perfusion pressure of the eye affects the retina although the eye is able to autoregulate its hemodynamics. Systemic hypoxemia (lung or heart disease) or a vascular disease in the retina can cause retinal hypoxia. All the hypoxia-dependent events in cells appear to share a common denominator: hypoxia-inducible factor (HIF), which is a heterodimeric transcription factor, a protein. HIF comprises a labile alpha subunit (1-3), which is regulated, and a stable beta subunit, which is constitutively expressed. Both are helix-loop-helix factors and belong to the PAS-domain family of transcription factors. Oxygen plays the key role in stabilizing HIF-1alpha and its function. When the oxygen tension is normal, HIF-1alpha is rapidly oxidized by hydroxylase enzymes, but when cells become hypoxic, HIF-1alpha escapes the degradation and starts to accumulate, triggering the activation of a large number of genes, like vascular endothelial growth factor (VEGF) and erythropoietin. HIF-1alpha has been shown to have, either clinically or experimentally, a mediating or contributing role in several oxygen-dependent retinal diseases such as von Hippel-Lindau, proliferative diabetic retinopathy, retinopathy of prematurity and glaucoma. In retinitis pigmentosa and high-altitude retinopathy, however, the evidence is still indirect. There are three different strategies available for treating retinal diseases, which have all shown promising results: retinal cell transplantation or replacement, gene replacement, and pharmacological intervention. Specifically, recent results show that the HIF pathway can be used as a therapeutic target, although there is still a long way to go from bench to clinic. HIF can be stabilized by inhibiting prolyl hydroxylase or by blocking the VHL:HIF-alpha complex if angiogenesis is the goal, as in retinitis pigmentosa. On the other hand, the downregulation of HIF has a pivotal role if we are to inhibit neovascularization, as in proliferative diabetic retinopathy. To date, several small-molecule inhibitors of HIF have been developed and are entering clinical trials. HIF is a remarkable example of a single transcription factor that can be regarded as a "master switch" regulating all the oxygen-dependent retinal diseases.
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PMID:Oxygen-dependent diseases in the retina: role of hypoxia-inducible factors. 1675 May 26

Copper promotion of angiogenesis has been known for more than two decades, but the mechanism of action of copper has not been explored until recently. Copper stimulation of factors involved in vessel formation and maturation, such as vascular endothelial growth factor (VEGF), is mainly responsible for its angiogenesis effect. Copper is required for the activation of hypoxia-inducible factor-1 (HIF-1), a major transcription factor regulating the expression of VEGF. Copper would be transported into nucleus by a copper chaperon for superoxide dismutase-1. Copper is required for HIF-1 interaction with the hypoxia-responsive element of the target genes and ensures the formation of HIF-1 transcriptional complex, thus activating the expression of target genes including VEGF. On the other hand, excess copper can stabilize HIF-1alpha, the rate-limiting component of HIF-1, leading to its accumulation in cytoplasm and thus HIF-1 activation. The essential role of copper in production of VEGF makes it implicated in anti-angiogenesis therapy, such as the application of copper chelators in cancer therapy. However, suppression of angiogenesis is involved in the progression of heart hypertrophy and its transition to heart failure, therefore copper supplementation improves hypertrophic heart disease conditions. This dilemma of copper implications in cancer therapy and heart hypertrophy dictates a comprehensive understanding of a patient's condition before an implementation of copper manipulation therapy for different diseases. In this context, a development of diagnosis for copper metabolic changes as well as a tissue-specific copper manipulation would greatly benefit patients with an implication of copper manipulation therapy.
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PMID:Role of copper in angiogenesis and its medicinal implications. 1935 87

ATP-sensitive potassium channels couple cell excitability to energy metabolism, thereby providing life-saving protection of stressed cardiomyocytes. The signaling for ATP-sensitive potassium channel expression is still unknown. We tested involvement of biochemical and biophysical parameters and potential transcription factors Forkhead box (FOX) and hypoxia-inducible factor (HIF-1alpha). Right atrial tissues were obtained during surgery from 28 children with heart disease. Expression of K(+)-inward-rectifier subunits Kir6.1/Kir6.2; sulfonyl urea receptors (SURs) SUR1A/B and SUR2A/B; and FOX class O (FOXO) 1, FOXO3, FOXF2, and HIF-1alpha were related to 31 parameters, including personal data, blood chemistry, and echocardiography. Venous hypoxemia (but not other ischemia indicators, such as venous hypercapnia or low glucose) predicts increased Kir6.1 (P<0.003) and Kir6.2 (P<0.03) protein. Kir6.1 associates with SUR2A/B mRNA (P<0.05) and correlates with FOXOs (P<0.002). FOXOs correlate with HIF-1alpha (P<0.01) and HIF-1alpha with venous hypoxemia (P<0.003). Electrophoretic mobility-shift assays suggest causal links among hypoxia, HIF-1alpha, FOXO1, and Kir6.1. To mimic mild ischemia encountered in some patients, cultured rat atrial myocytes were tested in hypoxia, hypercapnia, or low glucose, with normal conditions serving as the control. Mild hypoxia (24-hour) increases expression of HIF-1alpha, FOXO1, and SUR2A/B/Kir6.1 in culture (P<0.01), whereas hypercapnia and low glucose have no or opposite effects. Gene knockdown of HIF-1alpha or FOXO1 by small-interfering RNAs abolishes hypoxia-induced expression of FOXO1 and SUR2A/B/Kir6.1. These results suggest that low tissue oxygen determines increased expression of the atrial SUR2A/B/Kir6.1 gene via activation of HIF-1alpha-FOXO1. Because increased SUR2A/B/Kir6.1 has known survival benefits, this pathway offers novel therapeutic targets for children with heart disease.
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PMID:Central venous hypoxemia is a determinant of human atrial ATP-sensitive potassium channel expression: evidence for a novel hypoxia-inducible factor 1alpha-Forkhead box class O signaling pathway. 2021 66