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)

Ag-specific activation of T lymphocytes requires two signals, one by the TCR and a second by costimulatory molecules. In a CD4+ T helper cell-dependent experimental autoimmune myocarditis model, we provide genetic evidence that cardiac myosin-induced autoimmune myocarditis and the production of IgG auto-Abs is dependent on functional T cells and did not occur in mice lacking the tyrosine kinase p56lck or the tyrosine phosphatase CD45. By contrast, animals lacking the T cell-costimulatory molecule CD28 (CD28 -/-) developed autoimmune heart disease, although at significantly lower severity than in heterozygous littermates, and produced IgG auto-Abs depending on the concentration of the autoantigen administered. In addition, the isotypes of IgG auto-Abs specific for cardiac myosin differed between CD28 +/- and CD28 -/- mice. Whereas CD28 +/- mice predominantly produced Th2-mediated IgG1 auto-Abs, CD28 -/- mice produced predominantly IgG2a. These data suggest that CD28 costimulation plays a crucial role in induction and maintenance of autoimmune heart disease and that CD28 expression is required for predominant Th2-IgG1 responses in an autoimmune setting.
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PMID:Induction of autoimmunity in the absence of CD28 costimulation. 875 65

Broadly defined, phytoestrogens include isoflavones, coumestans, and lignans. A number of these compounds have been identified in fruits, vegetables, and whole grains commonly consumed by humans. Soybeans, clover and alfalfa sprouts, and oilseeds (such as flaxseed) are the most significant dietary sources of isoflavones, coumestans, and lignans, respectively. Studies in humans, animals, and cell culture systems suggest that dietary phytoestrogens play an important role in prevention of menopausal symptoms, osteoporosis, cancer, and heart disease. Proposed mechanisms include estrogenic and antiestrogenic effects, induction of cancer cell differentiation, inhibition of tyrosine kinase and DNA topoisomerase activities, suppression of angiogenesis, and antioxidant effects. Although there currently are no dietary recommendations for individual phytoestrogens, there may be great benefit in increased consumption of plant foods.
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PMID:Dietary phytoestrogens. 924 Sep 32

The presence of HS (heparan sulphate) proteoglycans on the cell surface and in the extracellular environment is critical to many physiological processes including the growth of new blood vessels from pre-existing vasculature (angiogenesis). A plethora of growth factors and their receptors, extracellular matrix molecules and enzymes bind to specific sites on the HS sugar chain. For example, HS proteoglycans have profound effects on the bioactivity of the key angiogenic factor VEGF (vascular endothelial growth factor) (VEGF(165)), affecting its diffusion, half-life and interaction with its tyrosine kinase receptors. A number of HS structural features that mediate the specific binding of VEGF(165), including sulphation requirements, have been determined. In parallel, zebrafish embryos were used as a vertebrate model system to study the role in vascular development of the biosynthetic enzymes that create these specific binding sites on HS. It was discovered that knockdown of one of the HS 6-O-sulphotransferases in zebrafish with morpholino antisense oligonucleotides reduced vascular branching and corresponded to changes in the HS structure. The roles of the extracellular 6-O-sulphatase enzymes, the sulfs, in vascular development are now being investigated. Both oligosaccharides and small molecule biosynthetic enzyme inhibitors could be valuable HS-based strategies for controlling aberrant angiogenesis in diseases as diverse as cancer and heart disease.
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PMID:The role of heparan sulphate proteoglycans in angiogenesis. 1670 84

Voltage-dependent calcium channels (VDCCs) play a pivotal role in normal excitation-contraction coupling in cardiac myocytes. These channels can be modulated through activation of beta-adrenergic receptors (beta-ARs), which leads to an increase in calcium current (I(Ca-L)) density through cardiac Ca(v)1 channels as a result of phosphorylation by cAMP-dependent protein kinase A. Changes in I(Ca-L) density and kinetics in heart failure often occur in the absence of changes in Ca(v)1 channel expression, arguing for the importance of post-translational modification of these channels in heart disease. The precise molecular mechanisms that govern the regulation of VDCCs and their cell surface localization remain unknown. Our data show that sustained beta-AR activation induces internalization of a cardiac macromolecular complex involving VDCC and beta-arrestin 1 (beta-Arr1) into clathrin-coated vesicles. Pretreatment of myocytes with pertussis toxin prevents the internalization of VDCCs, suggesting that G(i/o) mediates this response. A peptide that selectively disrupts the interaction between Ca(V)1.2 and beta-Arr1 and tyrosine kinase inhibitors readily prevent agonist-induced VDCC internalization. These observations suggest that VDCC trafficking is mediated by G protein switching to G(i) of the beta-AR, which plays a prominent role in various cardiac pathologies associated with a hyperadrenergic state, such as hypertrophy and heart failure.
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PMID:beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway. 2181 27

The treatment algorithm that has recently been developed at the 4th World Conference on Pulmonary Hypertension (PH) in Dana Point will contain a number of important innovations for patients with pulmonary arterial hypertension (PAH), but also for those with other forms of PH. In PAH patients, a targeted therapy with ERA or PDE5 inhibitors is now recommended for patients in functional class II. Combination therapy (ERA and/or PDE5i and/or prostanoids) is proposed if the clinical response to monotherapy is not adequate. In addition, supervised training programs are recommended for patients with PAH. For other forms of PH such as PH due to left heart disease or chronic lung disease, it remains valid that the underlying disease should be treated as efficiently as possible. However, a targeted PAH therapy may be beneficial in selected patients with "out of proportion PH", but these treatments should exclusively be initiated in expert centers. Pulmonary endarterectomy (PEA) remains the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). If patients are inoperable and/or if surgical treatment is not an option, targeted PAH therapy may be considered, but these patients should at present be included into clinical trials. Since there is currently no cure for PH/PAH, further development and progress in medical treatment are highly desirable. A number of promising novel compounds are currently under investigation. These include sGC stimulators, tyrosine kinase inhibitors, and serotonin antagonists.
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PMID:[Dana Point: what is new in the treatment of pulmonary hypertension?]. 1881 94

Type 2 diabetes is responsible for the increased prevalence of ischaemic heart disease, generally related to coronary artery disease, which is associated with increased morbidity and death in diabetic patients. Epidermal growth factor receptor (EGFR) tyrosine kinase, one of the many factors involved in cell growth and migration, has been shown to be key element in the development of microvessel myogenic tone. In a recent study, we have shown that microvascular dysfunction in type 2 diabetes is dependent on the exacerbation of the EGFR tyrosine kinase phosphorylation. Thus, further elucidation of this EGFR transactivation and down stream signalling will offer a new direction to investigate the mechanism of microvascular dysfunction responsible for heart disease that occurs in type 2 diabetes. In this review, we discuss the link between the EGFR transactivation and microvascular dysfunction that occurs in type 2 diabetes.
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PMID:Diabetes and microvascular pathophysiology: role of epidermal growth factor receptor tyrosine kinase. 1994 20

Pulmonary hypertension (PH) is a fatal disease caused by small pulmonary artery obstruction from vascular proliferation and remodeling. PH is characterized by elevated pulmonary arterial pressure and increased pulmonary vascular resistance, frequently leading to right-sided heart failure and death. The classification of PH has been recently updated to include 5 major categories of the disorder, are as: Group 1, pulmonary arterial hypertension (PAH); Group 2, PH due to left heart disease; Group 3, PH due to lung diseases and/or hypoxia; Group 4, chronic thromboembolic PH (CTEPH); and Group 5, others. Recently, significant progress has been made in the understanding of the pathophysiology, diagnosis and treatment of PH. Regarding the pathophysiology of the disorder, direct evidence for Rho-kinase activation in the pulmonary artery from PAH patients has been provided. Regarding diagnosis, optical coherence tomography is useful as a new differential diagnostic tool for distal type CTEPH vs. PAH. Regarding treatment, in addition to the conventional therapy, several new drugs are under clinical trial, including fasudil (a Rho-kinase inhibitor), riosiguat (a soluble guanylate cyclase activator), and imatinib (a tyrosine kinase inhibitor). In addition, pulmonary angioplasty and intensive immunosuppressive therapy may be effective for CTEPH and connective tissue disease-associated PAH, respectively. We briefly review the recent progress in the management of PH.
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PMID:Recent progress in the management of pulmonary hypertension. 2174 94

The HER family of tyrosine kinase receptors includes several members that are clinically important targets in cancer therapies, in particular HER1 (the EGF receptor) and HER2, other members include HER3 and HER4. Trastuzumab, a humanized monoclonal antibody and lapatinib, a tyrosine kinase inhibitor, are drugs that target HER2, which is highly expressed in 20-30% of breast cancers. Trastuzumab is recommended as an adjuvant therapy for lymph node positive, HER2-positive breast cancers, or node-negative cancer with high-risk of recurrence, as well as in stage IV cancers. One serious side effect of trastuzumab is cardiomyocyte dysfunction, resulting in reduced heart contractile efficiency. The incidence of collateral effects on the heart with trastuzumab therapy increases in people with cardiovascular risk factors, heart disease and when combined with other chemotherapeutics. When cardiotoxicity was observed with trastuzumab, several studies have addressed potential cardiac damage of trastuzumab itself and lapatinib. The differences in cardiovascular effects of these two compounds are somewhat unexpected and suggest distinct mechanisms of action, which have clear implications in clinical application and prevention of cardiotoxicity in cardio-oncological approaches.
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PMID:Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors. 2192 48

Cardiotoxicity associated with breast cancer treatment is an important concern in the oncology clinic. Different types of anti-cancer therapies have recorded high rates of cardiac dysfunction in treated patients. Cardiac dysfunction linked to anthracyclines--one of the most common conventional chemotherapies--has extensively been described and several mechanisms have been proposed, although their mode of action is not fully understood even in cancer cells. The mediation of cardiac damage by reactive oxygen species stress is a recent hypothesis that has attracted a lot of interest, since it might explain the tissue-specific toxic effects of anthracyclines in the heart. Regarding molecular targeted tyrosine kinase inhibitors used in patients with human epidermal growth factor receptor type 2+ tumours (e.g., trastuzumab, lapatinib), it is the blockage of survival pathways required for a normal heart development and function that seems to lead to cardiac pathology. Both types of breast cancer treatment appear to trigger cardiotoxicity synergically, being patients under adjuvant therapy closely monitored. Given the complex nature of heart failure and of the pathways altered by anti-cancer drugs, global gene expression regulation is key in the heart disease process. MicroRNAs have been demonstrated to be small molecules with big roles as essential gene expression modulators. The great potential of microRNAs as biomarkers in the cardio-oncology field needs to be further explored before new microRNA-based diagnostic and therapeutic tools can be developed.
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PMID:Breast cancer treatment and adverse cardiac events: what are the molecular mechanisms?. 2290 32

Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic factor, and its binding protein, placental growth factor (PlGF), are altered in women with preeclampsia. Recently, the sFlt-1/PlGF ratio has been shown to predict acute coronary syndrome in adults. However, few reports have described the use of the sFlt-1/PlGF ratio for evaluating an abnormal hemodynamic load in children with congenital heart disease (CHD). The sFlt-1/PlGF ratio was determined in 20 children with atrial septal defects (ASD), 26 children with ventricular septal defects (VSD), 57 children with tetralogy of Fallot (ToF), 35 children who were Fontan candidates (Fontan), and 14 controls. The preoperative sFlt-1/PlGF ratios in the ASD, VSD, and Fontan were significantly higher than those in the controls and were significantly decreased after surgical repair in the ASD and VSD. In the ToF, the sFlt-1/PlGF ratio was highest after first-stage repair and second-highest after final-stage palliation compared with the preoperative levels. The sFlt-1/PlGF ratio was highest after first-stage repair and much lower after final-stage palliation in the Fontan. Furthermore, these ratios correlated with the degree of the ventricular volume overload and hypoxia. Our study clearly demonstrated that the sFlt-1/PlGF ratio increases with volume overload and persistent hypoxia after surgery with CHD. These findings may prove useful in the management of CHD in children.
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PMID:Ratio between fms-like tyrosine kinase 1 and placental growth factor in children with congenital heart disease. 2538 29


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