Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increase in oxidative stress is suggested to be intimately involved in the pathogenesis of heart failure. Phenolic acids are widespread in plant foods; they contain important biological and pharmacological properties. This study evaluated the role of phenolic acids on the expression of antioxidant enzymes in the heart of male Sprague-Dawley rats. Gallic acid, ferulic acid and p-coumaric acid at a dosage of 100 mg kg(-1) body weight significantly increased the activities of cardiac superoxide dismutase, glutathione peroxidase (GPx) and catalase (CAT) as compared with control rats (P<.05). The changes in cardiac CuZnSOD, GPx and CAT mRNA levels induced by phenolic acids were similar to those noted in the enzyme activity levels. A significant (P<.05) increase in the GSH/GSSG ratio was observed in the heart of phenolic acid-treated rats. The heart homogenates obtained from rats that were administered phenolic acids displayed significant (P<.05) increases in capacity for oxygen radical absorbance compared with control rats. Immunoblot analysis revealed the increased cardiac total level of Nrf2 in phenolic acid-treated rats. Interestingly, phenolic acid-mediated antioxidant enzyme expression was accompanied by up-regulation of heme oxygenase-1. This study demonstrates that antioxidant enzymes in rat cardiac tissue can be significantly induced by phenolic acids following oral administration.
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PMID:Inducing gene expression of cardiac antioxidant enzymes by dietary phenolic acids in rats. 1854 98

The S-nitrosoglutathione-metabolizing enzyme, GSNO reductase (GSNOR), has emerged as an important regulator of protein S-nitrosylation. GSNOR ablation is protective in models of asthma and heart failure, raising the idea that GSNOR inhibitors might hold therapeutic value. Here, we investigated the effects of a small molecule inhibitor of GSNOR (GSNORi) in mouse RAW 264.7 macrophages. We found that GSNORi increased protein S-nitrosylation in cytokine-stimulated cells, and we utilized stable isotope labeling of amino acids in cell culture (SILAC) to quantify the cellular response to this "nitrosative stress". The expression of several cytokine-inducible immunomodulators, including osteopontin, cyclooxygenase-2, and nitric oxide synthase isoform 2 (NOS2), were decreased by GSNORi. In addition, selective targets of the redox-regulated transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-including heme oxygenase 1 (HO-1) and glutamate cysteine ligase modulatory subunit-were induced by GSNORi in a NOS2- and Nrf2-dependent manner. In cytokine-stimulated cells, Nrf2 protected from GSNORi-induced glutathione depletion and cytotoxicity and HO-1 activity was required for down-regulation of NOS2. Interestingly, GSNORi also affected a marked increase in NOS2 protein stability. Collectively, these data provide the most complete description of the global effects of GSNOR inhibition and demonstrate several important mechanisms for inducible response to GSNORi-mediated nitrosative stress.
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PMID:Proteomic characterization of the cellular response to nitrosative stress mediated by s-nitrosoglutathione reductase inhibition. 2862 76

This review focuses on cardiovascular protective effects of insulin-like growth factor (IGF)-1, provides a landscape of molecular mechanisms involved in cardiovascular alterations in patients and animal models with congenital and adult-onset IGF-1 deficiency, and explores the link between age-related IGF-1 deficiency and the molecular, cellular, and functional changes that occur in the cardiovascular system during aging. Microvascular protection conferred by endocrine and paracrine IGF-1 signaling, its implications for the pathophysiology of cardiac failure and vascular cognitive impairment, and the role of impaired cellular stress resistance in cardiovascular aging considered here are based on emerging knowledge of the effects of IGF-1 on Nrf2-driven antioxidant response.
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PMID:The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. 2245 68

Oxidative stress and inflammation are implicated in cardiovascular diseases such as atherosclerosis, reperfusion injury, hypertension, and heart failure. High levels of oxidative stress resulting from increased cardiac generation of reactive oxygen species (ROS) is thought to contribute to contractile and endothelial dysfunction, apoptosis and necrosis of myocytes, and extracellular matrix remodeling in the heart. ROS activate several transcription factors known as redox-regulated transcription factors, and these transcription factors play important roles in the pathophysiology of cardiovascular diseases. This review focuses on the pathological roles of environmental and redox stresses in cardiovascular diseases, especially severe cardiac dysfunction and the transition from compensated hypertrophy to heart failure. The aryl hydrocarbon receptor (AHR) and NF-E2 p45-related factor (Nrf2) are transcription factors involved in the regulation of drug-metabolizing enzymes. AHR has been studied as a receptor for environmental contaminants and as a mediator of chemical toxicity. However, other roles for AHR in cardiac and vascular development have recently been described. Moreover, Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes. The roles of these transcription factors, AHR and Nrf2 in angiogenesis are also discussed in this review.
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PMID:The pathological roles of environmental and redox stresses in cardiovascular diseases. 2327 40

The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer. Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication. The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs. In the present study, we demonstrate that 3,3'-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF). Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell. Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy.
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PMID:3,3'-Diindolymethane ameliorates adriamycin-induced cardiac fibrosis via activation of a BRCA1-dependent anti-oxidant pathway. 2337 55

Currently, the sole treatment option for patients with heart failure is transplantation. The battle of prolonging graft survival and modulating innate and adaptive immune responses is still being waged in the clinic and in research labs. The transcription factor Nrf2 controls major cell survival pathways and is central to moderating inflammation and immune responses. In this study the effect of Nrf2 levels in host recipient C57BL/6 mice on Balb/c allogeneic graft survival was examined. Importantly, Nrf2(-/-) recipient mice could not support the graft for longer than 7.5 days on average, whereas activation of Nrf2 by sulforaphane in Nrf2(+/+) hosts prolonged graft survival to 13 days. Several immune cells in the spleen of recipient mice were unchanged; however, CD11b(+) macrophages were significantly increased in Nrf2(-/-) mice. In addition, IL-17 mRNA levels were elevated in grafts transplanted into Nrf2(-/-) mice. Although Nrf2 appears to play a crucial role in graft survival, the exact mechanism is yet to be fully understood.
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PMID:Nrf2 is crucial to graft survival in a rodent model of heart transplantation. 2353 98

The cardiovascular system is susceptible to a group of diseases that are responsible for a larger proportion of morbidity and mortality than any other disease. Many cardiovascular diseases are associated with a failure of defenses against oxidative stress-induced cellular damage and/or death, leading to organ dysfunction. The pleiotropic transcription factor, nuclear factor-erythroid (NF-E) 2-related factor 2 (Nrf2), regulates the expression of antioxidant enzymes and proteins through the antioxidant response element. Nrf2 is an important component in antioxidant defenses in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure. Nrf2 is also involved in protection against oxidant stress during the processes of ischemia-reperfusion injury and aging. However, evidence suggests that Nrf2 activity does not always lead to a positive outcome and may accelerate the pathogenesis of some cardiovascular diseases (e.g., atherosclerosis). The precise conditions under which Nrf2 acts to attenuate or stimulate cardiovascular disease processes are unclear. Further studies on the cellular environments related to cardiovascular diseases that influence Nrf2 pathways are required before Nrf2 can be considered a therapeutic target for the treatment of cardiovascular diseases.
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PMID:Nrf2 and cardiovascular defense. 2369 Dec 61

The prevalence, incidence and mortality of all cardiovascular disorders (CVD) are two- to eightfold higher in persons with diabetes than in those without diabetes. Predicting and understanding the causes of CVD still represents an enormous challenge for clinical and basic cardiovascular science. Similarly, the fundamental mechanism by which diabetic patients are more prone to heart failure is unclear and prevention of such cardiac risk remains a major challenge for which new strategies are needed. Imbalance between free radicals and anti-oxidant defenses is associated with cellular dysfunctions leading to the pathophysiology of various diseases. Evidence suggests that diabetes is associated with a reduced overall antioxidant defense system and the increased oxidative stress. This may contribute to the pathogenesis of the diabetic complications, notably the emergence of premature atherosclerosis. The transcription factor NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) regulates the expression of many detoxifying genes such as catalase, superoxide dismutase, UDP-glucuronosyltransferase, c-glutamylcysteine synthetase, NAD(P)H quinone oxidoreductase 1, glutathione- S-transferase, glutathione peroxidase-1 and heme oxygenase-1. Polymorphic effects of these antioxidant genes and their regulatory regions have higher relevancy to the susceptibility to clinical conditions such as diabetes, obesity and cardiovascular diseases. Thus, the present review aims to explore the relationship between free radicals, diabetes and its associated complications with respect to the genetic makeup of Nrf2/ARE regulated genes in an effort to expand treatment options.
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PMID:Potential impact of genetic variants in Nrf2 regulated antioxidant genes and risk prediction of diabetes and associated cardiac complications. 2383 71

Heart failure (HF) is frequently the consequence of sustained, abnormal neurohormonal, and mechanical stress and remains a leading cause of death worldwide. The key pathophysiological process leading to HF is cardiac remodeling, a term referring to maladaptation to cardiac stress at the molecular, cellular, tissue, and organ levels. HF and many of the conditions that predispose one to HF are associated with oxidative stress. Increased generation of reactive oxygen species (ROS) in the heart can directly lead to increased necrosis and apoptosis of cardiomyocytes which subsequently induce cardiac remodeling and dysfunction. Nuclear factor-erythroid-2- (NF-E2-) related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant genes and other cytoprotective phase II detoxifying enzymes that are ubiquitously expressed in the cardiovascular system. Emerging evidence has revealed that Nrf2 and its target genes are critical regulators of cardiovascular homeostasis via the suppression of oxidative stress, which is the key player in the development and progression of HF. The purpose of this review is to summarize evidence that activation of Nrf2 enhances endogenous antioxidant defenses and counteracts oxidative stress-associated cardiac remodeling and HF.
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PMID:The role of Nrf2-mediated pathway in cardiac remodeling and heart failure. 2510 Nov 51

Protein quality control (PQC) acts to minimize the level and toxicity of malfolded proteins in the cell. It is performed by an elaborate network of molecular chaperones and targeted protein degradation pathways. PQC monitors and maintains protein homeostasis or proteostasis in the cells. Whilst chaperones may actively promote refolding of malfolded proteins, the malfolded proteins which cannot be correctly refolded are degraded by the ubiquitin proteasome system (UPS) and the autophagic-lysosome pathway (ALP). The UPS degrades individual misfolded protein molecules, whereas the ALP removes large and less soluble protein aggregates and organelles. Emerging evidence indicates that dysregulated and inadequate PQC play an important role in the pathogenesis of not only classic conformational disease but more common forms of cardiac pathology such as cardiac pathological hypertrophy and heart failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor of cellular defense, appears to regulate the USP and the ALP by directly controlling the expression of UPS- and ALP- related genes. This article highlights an emerging role of Nrf2 in the regulation of intracellular PQC as well as its potential involvement in cardiac pathology.
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PMID:Nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated protein quality control in cardiomyocytes. 2670 69


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