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)

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.
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PMID:Interleukin-1 and related proteins in cardiovascular disease in adults and children. 1177 30

The nonviral gene transfer technologies include naked DNA administration, electrical or particle-mediated transfer of naked DNA, and administration of DNA-synthetic macromolecule complex vectors. Each method has its advantage, such as low immunogenicity, inexpensiveness, ease in handling, etc., but the common disadvantage is that the transfection efficiency has been relatively poor as far as conventional plasmid vectors are involved. To improve the nonviral gene transfer systems, Epstein-Barr virus (EBV)-based plasmid vectors (also referred to EBV-based episomal vectors) have been employed. These vectors contain the EBNA1 gene and oriP element that enable high transfer efficiency, strong transgene expression and long term maintenance of the expression. In the current article, I review recent preclinical gene therapy studies with the EBV plasmid vectors conducted against various diseases. For gene therapy against malignancies, drastic tumor suppression was achieved by gancyclovir administrations following an intratumoral injection with an EBV plasmid vector encoding the HSV1-TK suicide gene. Equiping the plasmid with carcinoembryonic antigen (CEA) promoter sequences enabled targeted killing of CEA-positive tumor cells, which was not accomplished by conventional plasmid vectors without the EBV genetic elements. Transfection with an apoptosis-inducing gene was also effective in inhibiting tumors. Interleukin (IL)-12 and IL-18 gene transfer, either local or systemic, induced therapeutic antitumoral immune responses including augmentation of the cytotoxic T lymphocyte (CTL) and natural killer (NK) activities, while an autologous tumor vaccine engineered to secrete Th1 cytokines via the EBV system also induced growth retardation of tumors. Non-EBV conventional plasmids were much less effective in eliciting these therapeutic outcomes. Intracardiomuscular transfer of the beta-adrenergic receptor gene induced a significant elevation in cardiac output in cardiomyopathic animals, suggesting the usefulness of the EBV system in treating heart failure. The EBV-based nonviral delivery also worked as genetic vaccine that triggered prophylactic cellular and humoral immunity against acute lethal viral infection. All the nonviral delivery vehicles so far tested showed an improved transfection rate when combined with the EBV-plasmids. Collectively, the EBV-based plasmid vectors may greatly contribute to nonviral gene therapy against a variety of disorders, including malignant, congenital, chronic and infectious diseases.
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PMID:Improvement of nonviral gene therapy by Epstein-Barr virus (EBV)-based plasmid vectors. 1218 22

We investigated whether beta-adrenergic receptor (beta-AR) stimulation induces the expression of interleukin (IL)-18, a proinflammatory cytokine, in myocardium and in cardiac-derived endothelial cells (CDEC) via activation of nuclear factor (NF)-kappaB. Our results indicate that isoproterenol (ISO) activates NF-kappaB DNA binding activity, and induces myocardial and systemic elaboration of IL-18 via beta2-AR signaling. Furthermore, in CDEC, ISO increased basal and inducible promoter activities, increased IL-18 gene transcription and mRNA stability, and induced IL-18 expression via beta2-AR agonism. Signaling required GiPI3K, PI3K, Akt, IKK, and NF-kappaB. In conclusion, our results indicate for the first time that isoproterenol induces myocardial and systemic elaboration of IL-18 via a beta2-AR and NF-kappaB-dependent mechanism. Similar events may occur in heart failure, a disease state characterized by sustained beta-AR activation.
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PMID:Beta-adrenergic stimulation induces interleukin-18 expression via beta2-AR, PI3K, Akt, IKK, and NF-kappaB. 1517 7

Interleukin (IL)-18 is the interferon-gamma-inducing factor and has potent proinflammatory activities. IL-18 has been recently implicated in atherosclerotic plaque instability and myocardial ischemia-reperfusion injury. However, it is unknown whether IL-18 expression is increased in human myocardium or if it has any role in heart failure. We analyzed the expression of IL-18, its receptor IL-18Ralpha, and its endogenous inhibitor, IL-18 binding protein (IL-18BP) in myocardial tissue from patients with end-stage heart failure (ischemic or dilated cardiomyopathy) and controls by use of quantitative real-time reverse transcriptase polymerase chain reaction, Western blot or immunohistochemical techniques. Plasma levels of IL-18 were also determined in 48 patients with heart failure. IL-18 mRNA and protein levels were up-regulated in the myocardium of patients with ischemic cardiomyopathy. Both ischemic and dilated myocardium showed increased IL-18Ralpha levels, suggesting potential biological effects. In addition, mRNA levels of IL-18 BP were down-regulated in the failing myocardium. Finally, plasma IL-18 levels were significantly elevated in patients with heart failure and were higher in those who died at follow-up than in survivors. The results suggest a potential role for the immunoinflammatory IL-18 signaling pathway in the pathophysiology of heart failure and identify novel therapeutic targets for future testing.
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PMID:Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure. 1537 32

In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure.
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PMID:Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes. 1557 30

The nonviral gene delivery systems are usually not very effective in transferring gene into target cells, and the intensity and duration of the gene expression is very poor. The EBNA1/oriP maintain EBNA1/oriP-based plasmids as episome, contribute to nuclear transport of the plasmid and transcriptional up-regulation of target gene. The EBNA1/oriP based plasmid enhances the transfection rate as well as magnitude and longevity of gene expression. This article reviews recent preclinical gene therapy studies with the EBV plasmid vectors conducted against various diseases. For gene therapy against malignancies, the EBNA1/ oriP based plasmid encoding the HSV1-TK suicide gene was combined with a cationic polymer to transfer into HCC cell line. The expression level of TK gene was 100- to 1000-fold higher than the conventional plasmid. The sensitivity of HCC to ganciclovir (GCV) elevated several hundred-fold. The EBNA1/oriP based plasmid equipped with tumor specific promoter, such as CEA promoter, enabled targeted killing of CEA-positive tumor cell. Transfection of EBNA1/oriP based plasmid carrying IL-12 and IL-18 gene either locally, or systemically, induced therapeufic antitumor immune responses including augmentation of the cytotoxic T lymphocyte and natural killer activities and growth retardation of tumors. For gene therapy of congenital diseases and chronic diseases, the EBNA1/oriP based plasmid encoding the adenosine deaminase gene was transfered into human hematopoietic progenitor cells. The ADA activity was elevated 1.5-to 2-fold. Intracardiomuscrlar transfer of the EBNA1/oriP based plasmid encoding the beta-AR gene may be useful for the treatment of severe heart failure. Human tumor necrosis factoralpha (hTNFalpha) is one of the most important inflammatory cytokines. It has been implicated in many autoimmune and inflammatory diseases. sTNFR can efficiently neutralize the bioactivities of hTNFalpha. In primary study we cloned the chimeric protein sTNFR II-IgG Fc and expect to use it in the gene therapy of the inflammatory disease relative to TNF. In summary, The EBNA1/oriP based plasmid shows advantage in gene therapy of cancer, congenital and inflammatory diseases. Moreover, the EBNA1/oriP element may greatly contribute to the engineering of a human artificial chromosome, the ultimate device for controllable gene therapy.
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PMID:[Progress of EBNA1/oriP-based plasmid applied in gene therapy]. 1610 85

Apoptosis of cardiomyocytes is increased in heart failure and has been implicated in disease progression. The activation of "proapoptotic" caspases represents a key step in cardiomyocyte apoptosis. In contrast, the role of "proinflammatory" caspases (caspases 1, 4, 5, 11, 12) is unclear. Here, we study the cardiac function of caspase-1. Gene array analysis in a murine heart failure model showed upregulation of myocardial caspase-1. In addition, we found increased expression of caspase-1 protein in murine and human heart failure. Mice with cardiomyocyte-specific overexpression of caspase-1 developed heart failure in the absence of detectable formation of interleukin (IL)-1beta or IL-18 and inflammation. Transgenic caspase-1 induced primary cardiomyocyte apoptosis before structural and molecular signs of myocardial remodeling occurred. In contrast, deletion of endogenous caspase-1 was beneficial in the setting of myocardial infarction-induced heart failure. Furthermore, caspase-1-deficient mice were protected from ischemia/reperfusion-induced cardiomyocyte apoptosis. Studies in primary rat cardiomyocytes indicated that caspase-1 induces cardiomyocyte apoptosis primarily through activation of caspases-3 and -9. In contrast to previous findings, which imply a proinflammatory role of caspase-1, these data suggest a primary proapoptotic role for caspase-1 in cardiomyocytes. Our findings support a functional role for caspase-1-mediated myocardial apoptosis contributing to the progression of heart failure.
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PMID:A role for caspase-1 in heart failure. 1730 64

We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
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PMID:Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. 1840 98

We examined if a loss-of-function polymorphism in the P2X(7) receptor (1513C) corresponded with circulating interleukin(IL)-18 concentrations in heart failure (HF) patients. IL-18 values were significantly elevated in HF subjects compared to healthy control subjects. No association was seen between the polymorphism and IL-18 concentrations in HF patients. In HF patients, IL-18 values had an inverse relationship with ejection fraction, mean arterial pressure and body mass index, while high IL-18 concentrations were associated with increased mortality.
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PMID:Circulating interleukin-18 concentrations and a loss-of-function P2X7 polymorphism in heart failure. 1867 19

Cardiovascular disease (CVD) remains the leading cause of morbidity and premature mortality in both women and men in most industrialized countries, and has for some time also established a prominent role in developing nations. In fact, obesity, diabetes mellitus and hypertension are now commonplace even in children and youths. Regular exercise is rapidly gaining widespread advocacy as a preventative measure in schools, medical circles and in the popular media. There is overwhelming evidence garnered from a number of sources, including epidemiological, prospective cohort and intervention studies, suggesting that CVD is largely a disease associated with physical inactivity. A rapidly advancing body of human and animal data confirms an important beneficial role for exercise in the prevention and treatment of CVD. In Part 1 of this review we discuss the impact of exercise on CVD, and we highlight the effects of exercise on (i) endothelial function by regulation of endothelial genes mediating oxidative metabolism, inflammation, apoptosis, cellular growth and proliferation, increased superoxide dismutase (SOD)-1, down-regulation of p67phox, changes in intracellular calcium level, increased vascular endothelial nitric oxide synthase (eNOS), expression and eNOS Ser-1177 phosphorylation; (ii) vascular smooth muscle function by either an increased affinity of the Ca2+ extrusion mechanism or an augmented Ca2+ buffering system by the superficial sarcoplasmic reticulum to increase Ca2+ sequestration, increase in K+ channel activity and/or expression, and increase in L-type Ca2+ current density; (iii) antioxidant systems by elevation of Mn-SOD, Cu/Zn-SOD and catalase, increases in glutathione peroxidase activity and activation of vascular nicotinamide adenine dinucleotide phosphate [(NAD(P)H] oxidase and p22phox expression; (iv) heat shock protein (HSP) expression by stimulating HSP70 expression in myocardium, skeletal muscle and even in human leucocytes, probably through heat shock transcription factor 1 activity; (v) inflammation by reducing serum inflammatory cytokines such as high-sensitivity C-reactive protein (hCRP), interleukin (IL)-6, IL-18 and tumour necrosis factor-alpha and by regulating Toll-like receptor 4 pathway. Exercise also alters vascular remodelling, which involves two forms of vessel growth including angiogenesis and arteriogenesis. Angiogenesis refers to the formation of new capillary networks. Arteriogenesis refers to the growth of pre-existent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. Another aim of this review is to focus on exercise-related cardiovascular protection against CVD and associated risk factors such as aging, coronary heart disease, hypertension, heart failure, diabetes mellitus and peripheral arterial diseases mediated by vascular remodelling. Lastly, this review examines the benefits of exercise in mitigating pre-eclampsia during pregnancy by mechanisms that include improved blood flow, reduced blood pressure, enhanced placental growth and vascularity, increased activity of antioxidant enzymes, reduced oxidative stress and restored vascular endothelial dysfunction.
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PMID:Exercise, vascular wall and cardiovascular diseases: an update (Part 1). 1902 18


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