Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modulatory calcineurin-interacting proteins (MCIPs), also known as the Down syndrome critical region 1 (DSCR1) and DSCR1-like proteins, are a recently described family of small, structurally related proteins that are preferentially expressed in heart, skeletal muscle, and brain. MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure. Transcription of the mammalian MCIP1 gene is induced by calcineurin, suggesting that it functions as an endogenous feedback regulator of calcineurin signal transduction. Forced expression of human MCIP1 protein in the hearts of transgenic mice attenuates the hypertrophic response to a broad range of stimuli. This review summarizes work from a number of laboratories on the structure, regulation, and function of MCIP proteins.
Trends Cardiovasc Med 2003 Jan
PMID:The role of modulatory calcineurin-interacting proteins in calcineurin signaling. 1255 96

First identified in activated T cells, the calcium (Ca2+)-dependent transcription factor, nuclear factor of activated T cells (NFAT), has since been shown to play a role in nonimmune cells, including cells of the cardiovascular system. In arterial smooth muscle, the diverse array of calcium-signaling modalities, the functional interplay between smooth muscle and endothelial cells, and the influence of intravascular pressure on calcium and other signaling pathways creates a calcium-regulatory environment that is arguably unique. This review focuses on mechanisms that control the initial Ca2+/calcineurin-dependent events in NFAT activation, with a particular emphasis on NFAT regulation in native vascular smooth muscle. Also addressed is the role of additional mechanisms that act to modulate calcineurin-dependent NFAT nuclear import/export, mechanisms that may have particular relevance in this tissue.
Trends Cardiovasc Med 2003 Feb
PMID:NFAT regulation in smooth muscle. 1258 40

In order to investigate the signal transduction mechanisms of lysophosphatidic acid (LPA)-induced vascular smooth muscle (VSM) DNA synthesis, rat aortic A10 cells were used as an experimental model and [ H]-thymidine incorporation was used as an index of DNA synthesis. LPA caused dose- and time-dependent increase in DNA synthesis in A10 VSM cells. LPA (10 microM) also stimulated the activity of casein kinase II (CKII) in a time-dependent manner. The inhibitors of CKII, daidzein and 5,6-dichlorobenzimidazole riboside, diminished the LPA-induced increase in CKII activity and DNA synthesis. The LPA-stimulated activities of extracellularly regulated kinases (ERK) and p38 kinases as well as the stimulatory effects of LPA on DNA synthesis were blocked by ERK inhibitor, PD98059, and p38 kinase inhibitor, SB203580. The LPA-induced increase in intracellular free Ca and the LPA-induced DNA synthesis were not affected by Ca channel blockers, verapamil and diltiazem, as well as a Ca -dependent protein phosphatase (calcineurin) inhibitor, cyclosporine A. These data suggest that the LPA-induced DNA synthesis in VSM cells may be mediated by a signal transduction mechanism involving CKII, ERK, and p38 K.
J Cardiovasc Pharmacol 2003 Mar
PMID:Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth muscle cells. 1260 16

In the canine ventricular myocardium, endothelin-1 and the muscarinic agonist carbachol scarcely affect the basal force of contraction but do induce a pronounced negative inotropic effect in the presence of beta-adrenoceptor agonists. Experiments were performed to examine whether the protein phosphatase inhibitor cantharidin inhibits the negative inotropic effect induced by endothelin-1 and carbachol in isolated canine ventricular trabeculae. In the presence of 100 nM norepinephrine, endothelin-1 (10 nM) and carbachol (30 nM) decreased the norepinephrine-induced positive inotropic effect to about 40% of the norepinephrine-induced maximal response. Cantharidin at 10 microM affected neither the basal force of contraction nor the positive inotropic effect of 100 nM norepinephrine, but it did attenuate markedly the negative inotropic effect of endothelin-1. By contrast, the negative inotropic effect of carbachol was not affected by 10 microM cantharidin. At 30 microM, cantharidin induced a positive inotropic effect and enhanced the positive inotropic effect of norepinephrine by approximately 60%. Cantharidin (30 microM) markedly attenuated the negative inotropic effect of 30 nM carbachol and partially decreased the negative inotropic effect of 100 nM carbachol. The present results indicate that the activation of phosphatase that is susceptible to cantharidin is involved in both the endothelin-1-induced and the carbachol-induced negative inotropic effect. The observation that the negative inotropic effect of endothelin-1 is inhibited by cantharidin at 10 microM and that cantharidin does not affect the negative inotropic effect of carbachol supports the view that the extent of the contribution of phosphatase activation may be higher in the endothelin-1-induced negative inotropic effect than in the carbachol-induced negative inotropic effect.
J Cardiovasc Pharmacol 2003 Jan
PMID:Inhibitory action of the phosphatase inhibitor cantharidin on the endothelin-1-induced and the carbachol-induced negative inotropic effect in the canine ventricular myocardium. 1268 4

Chemical immunosuppression developed at the beginning of clinical transplantation remains the basis of immunosuppressive protocols used today. Clinical trials of new agents focus on the incremental improvement in one of four areas of immunotherapy: induction, basic maintenance, adjuvant and steroid therapy. Induction immunotherapy developments include the use of humanized antibodies, specific targets (basiliximab, daclizumab) and lymphocyte depletion (anti-thymocyte globulin, campath-1H). Promising results from pilot trials allow for subsequent low dose maintenance monotherapy. New inhibitors of calcineurin isoforms (ISATx247) may disassociate the anti-rejection effect from the toxicity of conventional calcineurin inhibitors. Revived investigation of older anti-proliferative or anti-metabolite drugs (rapamycin, mycophenolic acid, leflunomide) show promise in preventing B-cell responses and reducing chronic rejection but development of derivatives (everolimus, mycophenolate mofetil, ERL 080, MNA 279, MNA 715) may have a stronger commercial than experimental basis. Trials of steroid immunotherapy have focused on steroid elimination but trial of newer locally active steroids may be beneficial.
Curr Drug Targets Cardiovasc Haematol Disord 2002 Dec
PMID:New immunosuppressants in clinical trial. 1276 49

Protein kinase C (PKC) and calcineurin are known to play a pivotal role in the development of cardiomyocyte growth. However, its role in Isoproterenol-induced (Iso) cardiac hypertrophy has not been characterized so far and were focus of the current study. After chronic beta-adrenergic stimulation of male Wistar rats with Iso (2mg/kg x day) for 2 and 7 days using osmotic minipumps, we determined a) cardiac PKC-activity, b) the expression of cardiac PKC isozymes (PKC-alpha, PKC-delta and PKC-epsilon) both at the protein and the mRNA-level and c) the expression of calcineurin using Western blot analysis. Iso-treatment for 2 and 7 days results in cardiac hypertrophy with an increase of the heart weight-to-body weight ratio by 36% and 27%. Iso-induced myocardial growth was associated with an enhanced total PKC-activity and a significant increased protein expression of cytosolic PKC-alpha (day 2: +38%; day 7: +43%), PKC-delta (day 2: 85%; day 7: +78%) and PKC-epsilon (day 7: +58%). The protein amount of calcineurin was not significantly altered by Iso compared with sham-operated controls. The increased expression of PKC-alpha, PKC-delta and PKC-epsilon in the cytosol was paralleled by a transcriptional upregulation of the absolute mRNA-levels of these PKC-isozymes as determined by quantitative RT-PCR.
J Cardiovasc Pharmacol 2003 Jun
PMID:Regulation of protein kinase C isozyme and calcineurin expression in isoproterenol induced cardiac hypertrophy. 1516 65

The purpose of this review is to highlight those circulating molecules, membrane receptors, and signaling pathways that initiate, potentiate, or conversely, inhibit apoptosis within cardiomyocytes. This review focuses on pathways directly related to the failing heart and discusses the limitations of current methodologies for assessing cardiomyocellular apoptosis. It is important to note that the adrenergic, reactive oxygen species, and proinflammatory cytokine signaling pathways are not the only pro-apoptotic pathways active in the myocardium, nor are IL-6-related cytokine, calcineurin, and IGF-1/PI3K/Akt signaling pathways the only anti-apoptotic pathways active in the myocardium. However, they are among the best-characterized apoptosis-mediating pathways and therefore they may serve as foundation for future studies aimed at identifying novel apoptotic regulating pathways active in cardiomyocytes. Considering the short history of studying cardiomyocellular apoptosis, a tremendous body of knowledge has been collected. Understandably, much more work remains. Tomorrow's studies must (1) continue to examine the signaling pathways mediating cardiomyocellular apoptosis by focusing on the links to the ubiquitous apoptosis effectors, (2) use the expanding body of knowledge to develop more specific inhibitors of apoptosis, and then (3) confirm the causal relationship of cardiomyocellular apoptosis and cardiac dysfunction in physiologic models of cardiac challenge.
Cardiovasc Toxicol 2003
PMID:The balance between pro-apoptotic and anti-apoptotic pathways in the failing myocardium. 1455 86

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney's ability to adjust to changes in serum tonicity. Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.
Am J Cardiovasc Drugs 2004
PMID:Calcineurin inhibitor-associated early renal insufficiency in cardiac transplant recipients: risk factors and strategies for prevention and treatment. 1496 63

Cardiac hypertrophy occurs in a number of disease states associated with chronic increases in cardiac work load. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure. Much investigation has focused on the signaling pathways controlling cardiac hypertrophy at the level of the single cardiac myocyte. One prohypertrophic pathway that has received much attention involves the ubiquitously expressed Ca2+/calmodulin-activated phosphatase calcineurin. Upon activation by Ca2+, calcineurin dephosphorylates nuclear factor of activated T cell (NFAT) transcription factors, leading to their nuclear translocation. As common in complex biological systems, cardiac hypertrophy is controlled simultaneously by stimulatory (prohypertrophic) and counter-regulatory (antihypertrophic) pathways. Given the potent prohypertrophic effects of the Ca2+-calcineurin-NFAT pathway in cardiac myocytes, it is not surprising that the activity of this pathway is tightly controlled at multiple levels. Inhibitory mechanisms upstream (nitric oxide (NO), cGMP, cGMP-dependent protein kinase type I (PKG I), heme oxygenase-1 (HO-1), biliverdin, carbon monoxide (CO)) and downstream from calcineurin (glycogen synthase kinase-3 (GSK3), c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinase (MAPKs)) have been described. Moreover, several inhibitors directly target calcineurin enzymatic activity (cyclosporine A (CsA), tacrolimus (FK506), calcineurin-binding protein-1 (Cabin-1)/calcineurin-inhibitory protein (Cain), A-kinase-anchoring protein-79 (AKAP79), calcineurin B homology protein (CHP), MCIPs, VIVIT). Considering the dominant role of the calcineurin pathway in cardiac hypertrophy and failure, calcineurin-inhibitory strategies may lead to the identification of novel therapeutic approaches for patients with cardiac disease.
Cardiovasc Res 2004 Aug 15
PMID:Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes. 1527 70

Prolonged cardiac hypertrophy of pathologic etiology is associated with arrhythmia, sudden death, decompensation, and dilated cardiomyopathy. In an attempt to understand the mechanisms that underlie the hypertrophic response, extensive investigation has centered on a characterization of the molecular pathways that initiate or maintain the pathologic growth of individual cardiac myocytes. While a large number of signal transduction cascades have been identified as critical regulators of cardiac hypertrophy, here the scientific evidence implicating the protein phosphatase calcineurin (PP2B) and the mitogen-activated protein kinases (MAPK) as co-regulators of reactive hypertrophy will be discussed. Gain- and loss-of-function studies in genetically altered mice and in cultured cardiomyocytes have demonstrated the necessity and sufficiency of calcineurin to regulate pathologic cardiac hypertrophy. However, using similar approaches, the hypertrophic regulatory role attributed to various branches of the MAPK signaling pathway has been less conclusive, although a loose consensus suggests that the c-Jun N-terminal kinases (JNK) and p38 kinases function as mediators of dilated cardiomyopathy, while extracellular signal-regulated kinases (ERKs) function as regulators of hypertrophy. More recently, the actions of calcineurin and MAPK signaling pathways have been shown to be co-dependent such that unitary activation of calcineurin in myocytes leads to up-regulation in ERK and JNK signaling, but down-regulation in p38 signaling. Conversely, unitary activation of JNK or p38 in cardiac myocytes leads to down-regulation of calcineurin effectiveness by directly antagonizing nuclear factor of activated T cells (NFAT) nuclear occupancy. Thus, an emerging paradigm suggests that calcineurin-NFAT and MAPK signaling pathways are inter-dependent and together orchestrate the cardiac hypertrophic response.
Cardiovasc Res 2004 Aug 15
PMID:Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. 1527 72


<< Previous 1 2 3 4 5 Next >>