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)

Mice deficient for the transcription factor NFATc1 fail to form pulmonary and aortic valves, a defect reminiscent of some types of congenital human heart disease. We examined the mechanisms by which NFATc1 is activated and translocated to the nucleus in human pulmonary valve endothelial cells to gain a better understanding of its potential role(s) in post-natal valvular repair as well as valve development. Herein we demonstrate that activation of NFATc1 in human pulmonary valve endothelial cells is specific to vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2. VEGF-induced NFATc1 nuclear translocation was inhibited by either cyclosporin A or a calcineurin-specific peptide inhibitor; these findings suggest that VEGF stimulates NFATc1 nuclear import in human pulmonary valve endothelial cells by a calcineurin-dependent mechanism. Importantly, both cyclosporin A and the calcineurin-specific peptide inhibitor reduced VEGF-induced human pulmonary valve endothelial cell proliferation, indicating a functional role for NFATc1 in endothelial growth. In contrast, VEGF-induced proliferation of human dermal microvascular and human umbilical vein endothelial cells was not sensitive to cyclosporin A. Finally, NFATc1 was detected in the endothelium of human pulmonary valve leaflets by immunohistochemistry. These results suggest VEGF-induced NFATc1 activation may be an important mechanism in cardiac valve maintenance and function by enhancing endothelial proliferation.
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PMID:NFATc1 mediates vascular endothelial growth factor-induced proliferation of human pulmonary valve endothelial cells. 1242 39

A subset of cyclin-dependent protein kinases--Cdk7, Cdk8, and Cdk9--participates directly, in complex ways, with the fundamental machinery for gene transcription, as elements of general transcription factors whose substrate is the C-terminal domain (CTD) of RNA polymerase II. Here, we review recent data implicating the CTD kinase Cdk9 as a critical determinant of cardiac hypertrophy, in vitro and in vivo. Diverse trophic signals that increase cardiac mass all activated Cdk9 (work load, the small G-protein Gaq, and the calcium-dependent phosphatase calcineurin in mouse myocardium; endothelin-1, a hypertrophic agonist, in cultured cardiomyocytes). Little or no change occurred in levels of the kinase or its activator, cyclin T. Instead, in all four hypertrophic models, Cdk9 activation involves the dissociation of 7SK small nuclear RNA (snRNA), an endogenous inhibitor. In culture, dominant-negative Cdk9 blocked ET-1-induced hypertrophy, whereas an anti-sense "knockdown" of 7SK snRNA provoked spontaneous cell growth. In trans-genie mice, concordant with these results, activation of Cdk9 activity via cardiac-specific overexpression of cyclin Tl suffices to provoke hypertrophy. Together, these findings implicate Cdk9 activity as a pivotal regulator of pathophysiological heart growth. Because hypertrophy, in turn, is a cardinal risk factor for developing cardiac pump failure, these results support the logic of examining Cdk9 as a potential drug target in heart disease.
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PMID:Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. 1269 56

This review focuses on the molecular determinants of the duration of the QT interval as measured on by electrocardiography in normal subjects and during cardiac hypertrophy and failure. (a) In control conditions, on a single cell, the shape and duration of the action potential is the result of a balance between different ion currents which in turn were determined by the number of functional channels. On multicellular preparations the QT duration also represents the repolarization time; nevertheless it is modified by the transmural gradients. On body-surface electrocardiography the duration of the QT interval depends also of an additional factor: the spatial three-dimensional projection of the electrical waves vectors, which makes any determination of the epicardial dispersion by measuring QT interval dispersion questionable. (b) The enhanced action potential duration is well documented in cardiac hypertrophy and heart failure and is usually caused by a reduction in outward current densities in most of the species except mice. Among these currents I(tO) is the most frequently altered, especially in humans. Such an altered current density is caused by a diminished expression of the genes encoding either the ion channel subunits or regulatory proteins, such as KChIP2. In addition, hypertrophy modifies or even reverses the transmural gradient. In human and rats hypertensive cardiopathy is associated with a prolongation of the QT interval duration. The reduction in I(tO) is likely to be adaptive; it participates in the slowing of the cardiac cycle and reflects the fetal genetic reprogramming. Recent data also suggest that a reduction in the transient outward K(+) current density triggers protein synthesis through an activation of the calcineurin pathways. Thus a prolongation of the QT interval is not only inherited or drug-induced; it is also an essential component of the adaptive process in chronic mechanical overload. It is fundamentally incorrect to measure QT dispersion on a surface electrocardiography, but the mean QT interval may provide information concerning the progression of the disease, just as, and with the same restrictions, in the case of the quantification of V(max).
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PMID:The long QT interval is not only inherited but is also linked to cardiac hypertrophy. 1275 Aug 20

Cardiac hypertrophy is a leading predicator of progressive heart disease that often leads to heart failure and a loss of cardiac contractile performance associated with profound alterations in intracellular calcium handling. Recent investigation has centered on identifying the molecular signaling pathways that regulate cardiac myocyte hypertrophy, as well as the mechanisms whereby alterations in calcium handling are associated with progressive heart failure. One potential focal regulator of cardiomyocyte hypertrophy that also responds to altered calcium handling is the calmodulin-activated serine/threonine protein phosphatase calcineurin (PP2B). Once activated by increases in calcium, calcineurin mediates the hypertrophic response through its downstream transcriptional effector nuclear factor of activated T cells (NFAT), which is directly dephosphorylated by calcineurin resulting in nuclear translocation. While previous studies have convincingly demonstrated the sufficiency of calcineurin to mediate cardiac hypertrophy and progressive heart failure, its necessity remains an area of ongoing investigation. Here we weigh an increasing body of literature that suggests a causal link between calcineurin signaling and the cardiac hypertrophic response and heart failure through the use of pharmacologic inhibitors (cyclosporine A and FK506) and genetic approaches. We will also discuss the manner in which calcineurin-NFAT signaling is negatively regulated in the heart through a diverse array of kinases and inhibitory proteins. Finally, we will discuss emerging theories as to the mechanisms whereby alterations in intracellular calcium handling might stimulate calcineurin within the context of a contractile cell continually experiencing calcium flux.
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PMID:Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. 1533 66

Post-transplantation diabetes mellitus (PTDM) is defined as sustained hyperglycemia developing in any patient without history of diabetes before transplantation, that meets the current diagnostic criteria by the American Diabetes Association or the World Health Organization. Several risk factors have been identified: age, nonwhite ethnicity, and glucocorticoid therapy for rejection and chronic immunosuppression with cyclosporine and especially tacrolimus. The pathophysiology of this condition resembles that of type 2 diabetes mellitus: pretransplantation end-stage liver/renal and heart disease are insulin-resistant states, and after transplantation, glucocorticoids induce further peripheral insulin insensitivity. The "second hit" appears to be an acquired (yet reversible) insulin secretion defect resulting from the calcineurin inhibitors cyclosporine and tacrolimus. An international panel of experts has recently published the proceeding of a Consensus Conference proposing strategies for the screening, prevention and management of PTDM. Future directions include pre- and post-transplantation glucose load testing for high-risk individuals and pharmacological agents to decrease insulin resistance and to preserve beta-cell function.
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PMID:Post-transplantation diabetes mellitus. 1571 25

There is great interest in deciphering mechanisms of maladaptive remodeling in cardiac hypertrophy in the hope of affording clinical benefit. Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy. However, little is known about the interaction-if any-between these important signaling molecules in hypertrophic heart disease. In this study, we examined the molecular interplay among these molecules, finding that Rho family guanosine triphosphatase signaling occurs either downstream of calcineurin or as a required, parallel pathway. It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition blocks hypertrophy, and we report here that "statin" therapy effectively suppresses small G protein activation and blunts hypertrophic growth in vitro and in vivo. Importantly, despite significant suppression of hypertrophy, clinical and hemodynamic markers remained compensated, suggesting that the hypertrophic growth induced by this pathway is not required to maintain circulatory performance.
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PMID:Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*. 1635 80

Calsarcins comprise a novel family of muscle-specific calcineurin-interacting proteins and play an important role in modulating both the function and substrate specificity of calcineurin in muscle cells. In this study, we cloned and characterized calsarcins from pig muscle. The deduced amino acid sequences of porcine calsarcin-1 (CS-1), calsarcin-2 (CS-2), and calsarcin-3 (CS-3) share the same putative calcineurin and alpha-actinin binding regions. Radiation hybrid mapping data indicate that CS-1 and CS-2 map to q2.1-2.5 of pig chromosome 8 (SSC8) and q2.4 of pig chromosome 14 (SSC14), respectively. The mRNA expressions of both CS-1 and CS-2 are regulated in skeletal muscle similarly during postnatal development but not during prenatal development, indicating differences in function, additionally demonstrated by minute differences in cellular localization within Pig Kidney Epithelial cells (PK15). We provide the first evidence that CS-1 is abundantly expressed in porcine heart and has an expression pattern similar to the human gene. This result suggests that the pig may be a suitable animal model to study the function of calsarcins in human heart disease.
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PMID:Characterization of different expression patterns of calsarcin-1 and calsarcin-2 in porcine muscle. 1657 46

A central feature of heart disease is a molecular remodeling of signaling pathways in cardiac myocytes. This study focused on novel molecular elements of MAPK-mediated alterations in the pattern of gene expression of the protein phosphatase 2A (PP2A). In an established model of sustained JNK activation, a 70% decrease in expression of the targeting subunit of PP2A, B56alpha, was observed in either neonatal or adult cardiomyocytes. This loss in protein abundance was accompanied by a decrease of 69% in B56alpha mRNA steady-state levels. Given that the 3'-untranslated region of this transcript contains adenylate-uridylate-rich elements known to regulate mRNA degradation, experiments explored the notion that instability of B56alpha mRNA accounts for the response. mRNA time-course analyses with real-time PCR methods showed that B56alpha transcript was transformed from a stable (no significant decay over 1 h) to a labile form that rapidly degraded within minutes. These results were supported by complementary experiments that revealed that the RNA-binding protein AUF1, known to destabilize target mRNA, was increased fourfold in JNK-activated cells. A variety of other stress-related stimuli, such as p38 MAPK activation and phorbol ester, upregulated AUF1 expression in cultured cardiac cells as well. In addition, gel mobility shift assays demonstrated that p37AUF1 binds with nanomolar affinity to segments of the B56alpha 3'-untranslated region. Thus these studies provide new evidence that signaling-induced mRNA instability is an important mechanism that underlies the changes in the pattern of gene expression evoked by stress-activated pathways in cardiac cells.
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PMID:JNK activation decreases PP2A regulatory subunit B56alpha expression and mRNA stability and increases AUF1 expression in cardiomyocytes. 1660 88

Fast transient outward potassium currents (I(to,f)) are critical determinants of regional heterogeneity of cardiomyocyte repolarization as well as cardiomyocyte contractility. Additionally, I(to,f) densities are markedly down-regulated in cardiac hypertrophy and heart disease, conditions associated with activation of the serine/threonine phosphatase calcineurin (Cn). In this study, we investigated the regulation of I(to,f) expression by Cn in cultured neonatal rat ventricular myocytes (NRVMs) with and without alpha(1)-adrenoreceptor stimulation with phenylephrine (PE). Overexpression of constitutively active Cn in NRVMs induced hypertrophy and caused profound increases in I(to,f) density as well as Kv4.2 mRNA and protein expression and promoter activity, without affecting Kv4.3 or KChIP2 levels. The effects of Cn on hypertrophy, I(to,f), and Kv4.2 transcription were associated with NFAT activation and were abrogated by NFAT inhibition. Despite activating Cn and inducing hypertrophy in NRVMs, PE resulted in profound down-regulation of I(to,f) densities as well as Kv4.2, Kv4.3, and KChIP2 expression. Although hypertrophy and NFAT activation were inhibited by the Cn inhibitory peptide CAIN, I(to,f) and Kv4.2 expression were further reduced by CAIN, whereas Cn overexpression eliminated PE-induced reductions in I(to,f) and Kv4.2 expression without affecting Kv4.3 or KChIP2 levels. We conclude that Cn increases cardiac I(to,f) densities by positively regulating Kv4.2 gene transcription. Consistent with this conclusion, we found that I(to,f) was increased in myocytes isolated from young mice overexpressing Cn prior to the development of heart disease. This positive regulation of Kv4.2 transcription by Cn activation is expected to minimize the reductions in I(to,f) and Kv4.2 expression observed in hypertrophic cardiomyocytes.
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PMID:Calcineurin increases cardiac transient outward K+ currents via transcriptional up-regulation of Kv4.2 channel subunits. 1706 Mar 17

Diverse forms of injury and stress evoke a hypertrophic growth response in adult cardiac myocytes, which is characterized by an increase in cell size, enhanced protein synthesis, assembly of sarcomeres, and reactivation of fetal genes, often culminating in heart failure and sudden death. Given the emerging roles of microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs that were regulated during cardiac hypertrophy and heart failure. We describe >12 miRNAs that are up- or down-regulated in cardiac tissue from mice in response to transverse aortic constriction or expression of activated calcineurin, stimuli that induce pathological cardiac remodeling. Many of these miRNAs were similarly regulated in failing human hearts. Forced overexpression of stress-inducible miRNAs was sufficient to induce hypertrophy in cultured cardiomyocytes. Similarly, cardiac overexpression of miR-195, which was up-regulated during cardiac hypertrophy, resulted in pathological cardiac growth and heart failure in transgenic mice. These findings reveal an important role for specific miRNAs in the control of hypertrophic growth and chamber remodeling of the heart in response to pathological signaling and point to miRNAs as potential therapeutic targets in heart disease.
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PMID:A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. 1710 80


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