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)

The success of cardiac transplantation has been largely attributable to the development of effective immunosuppressive regimens. The calcineurin inhibitors were pivotal in reducing the frequency of acute rejection and improving early survival. Newer agents, including mycophenolate mofetil and proliferation signal inhibitors, show some promise in further reducing episodes of acute allograft rejection and also having a significant impact on reducing transplant vasculopathy. The role of cytolytic induction therapy remains unclear, although its use may be most appropriate in the high risk presensitized transplant recipient. While the endomyocardial biopsy remains the gold standard for the diagnosis of acute allograft rejection, its invasive nature makes the test suboptimal. The presence of biopsy 'negative' rejection has also led to an appreciation for the role of antibody-mediated rejection in cardiac allograft dysfunction. Effective noninvasive evaluation of allograft rejection remains the ultimate challenge. While imaging technologies have some utility because of their ease of use, more sophisticated techniques such as gene-expession analysis from peripheral blood may show the greatest promise. Management of established acute allograft rejection has significantly improved with our understanding of the immune mechanisms involved. Therapies may be targeted specifically at cellular or humoral components of the immune system.
Semin Thorac Cardiovasc Surg 2004
PMID:Immunosuppression, diagnosis, and treatment of cardiac allograft rejection. 1563 44

Recent studies have indicated that caveolae are enriched in a variety of signaling molecules, some of which are associated with cardiomyocyte hypertrophy. Caveolin-3, a major constituent of cardiac caveolae, has been suggested to interact with several signaling molecules. We investigated the morphologic changes of caveolae and caveolin-3 expression in hypertrophied cardiomyocytes induced by an alpha1-adrenergic agonist. Cultured rat neonatal cardiomyocytes were used for the experiments. Phenylephrine induced cellular hypertrophy associated with an increase of the number of caveolae and an up-regulation of caveolin-3. Although PMA increased the number of caveolae and the caveolin-3 expression, the extent of these up-regulations was less than that by phenylephrine. Moreover, ionomycin increased the number of caveolae and up-regulated caveolin-3 as much as phenylephrine. Phenylephrine-induced up-regulations of caveolae and caveolin-3 expression were inhibited by BAPTA, suggesting that the intracellular Ca2+ is involved in those regulations. Inhibitors of calcineurin and Ca2+calmodulin-dependent kinase II attenuated the phenylephrine-induced up-regulation of caveolin-3. In pressure-overloaded rat hearts, caveolin-3 protein levels were increased compared with sham-operated rats. In conclusion, the number of caveolae and the expression of caveolin-3 were up-regulated in rat hypertrophied cardiomyocytes, possibly via the alterations of intracellular Ca2+ and protein kinase C.
J Cardiovasc Pharmacol 2005 Mar
PMID:Behavior of caveolae and caveolin-3 during the development of myocyte hypertrophy. 1572 44

Protein turnover represents the balance between protein synthesis and degradation. It can be controlled quantitatively, for instance by an activation of protein synthesis during cardiac hypertrophy or by activating protein degradation during ventricular unloading. It can also be regulated qualitatively by changing the steady state concentration of specific proteins and enzymes. The recent literature points to an emerging role for the mammalian target of rapamycin (mTOR) and for the ubiquitin-proteasome system (UPS) in this process, and both pathways interact in the regulation of cell growth and survival. We highlight the critical role played by such interaction in different cellular functions, including insulin signaling, stress response to hypoxia, adaptation to variations in workload, regulation of protein phosphatase activity, apoptosis and post-ischemic recovery. A deregulation of these pathways participates in the mechanisms of cardiac ischemia, hypertrophy and failure, and controlling their activity represents an opportunity for novel therapeutic avenues.
Cardiovasc Res 2005 Nov 01
PMID:Protein turnover in cardiac cell growth and survival. 1606 Dec 15

Chronic rejection remains a major complication in solid organ transplantation. Host alloreactive T cells (TC) can be activated by donor dendritic cells (DCs; direct allorecognition) or by recipient DCs (indirect allorecognition). A fundamental aspect of DC function is vascular invasion to present donor antigens to recipient naive TC in secondary lymphoid organs. We investigated the impact of calcineurin inhibitors on DC binding and transmigration to allogeneic human microvascular endothelial cells (ECs) with and without blocking of specific adhesion molecules. Recipient immature DCs were generated by culturing CD14 human peripheral blood monocytes with GM-CSF and IL-4. DC adhesion and transmigration were investigated on allogeneic ECs preincubated with increasing concentrations of cyclosporine and tacrolimus. Experiments were repeated in the presence of blocking antibodies against LFA-1, PECAM-1, VCAM-1, and ICAM-1. Endothelial stimulation with cyclosporine A (100 and 300 ng/mL) and tacrolimus (15 ng/mL) significantly enhanced DC-EC adhesion and transmigration (P<0.01). LFA-1 blockade on DCs significantly reduced cyclosporine- and tacrolimus-induced DC adhesion (P<0.001). VCAM-1 blockade on ECs partially reversed cyclosporine-induced DC adhesion (P<0.001), whereas DC adhesion under tacrolimus exposure was significantly decreased by ICAM-1 (P<0.01) and PECAM-1 (P<0.001) blockade. DC binding and transmigration on allogeneic ECs exposed to calcineurin inhibitors is concentration-dependently increased. Different adhesion molecule patterns on ECs are responsible for enhanced DC invasion under cyclosporine and tacrolimus exposure. We speculate that long-term immunosuppression mediates enhanced invasion of recipient DCs to the donor organ and therefore may aggravate chronic rejection.
J Cardiovasc Pharmacol 2005 Sep
PMID:Dendritic cell adhesion is enhanced on endothelial cells preexposed to calcineurin inhibitors. 1611 27

Calreticulin is a Ca(2+)-binding chaperone of the sarcoplasmic/endoplasmic reticulum. It is an important Ca(2+) buffer, a regulator of Ca(2+) homeostasis, and a component of protein quality control processes in the secretory pathway. Calreticulin is essential for cardiac development; its gene is tightly regulated during cardiogenesis, and in the absence of calreticulin, cardiac development is impaired. The protein is highly expressed in the developing heart and down-regulated after birth in the healthy mature heart. Overexpression of calreticulin in postnatal heart leads to bradyarrhythima and complete heart block, followed by sudden death. The calreticulin gene is a target of transcription factors involved in fetal cardiac program (Nkx2.5, myocardin, myocyte enhancer factor 2C, and GATA6). Calreticulin works upstream of calcineurin and myocyte enhancer factor 2C in a Ca(2+)-dependent signal transduction cascade linking the endoplasmic reticulum and the nucleus during cardiac development.
Trends Cardiovasc Med 2006 Apr
PMID:Assembling pieces of the cardiac puzzle; calreticulin and calcium-dependent pathways in cardiac development, health, and disease. 1654 85

The success of cardiac transplantation is largely attributable to the development of effective immunosuppressive regimens. The introduction of calcineurin inhibitors was pivotal in reducing the frequency of acute rejection and improving early survival. Newer agents, including mycophenolate mofetil (MMF) and proliferation-signal inhibitors, have shown promise in further reducing acute-rejection rates and, notably, reducing the frequency of cardiac allograft vasculopathy, which limits long-term graft survival. The introduction of first-year intravascular ultrasonography results as a surrogate marker for outcome after cardiac transplantation has helped assessment of the efficacy of immunosuppressive medications. Proliferation-signal inhibitors and MMF were shown by this imaging method to reduce cardiac allograft vasculopathy. The combination of these drugs, in tandem with the weaning of patients off calcineurin inhibitors, has been shown to reverse calcineurin-inhibitor-related nephrotoxic effects. A randomized trial that compared three of the more common immunosuppressive regimens suggested that tacrolimus and MMF are associated with a reduction in the frequency of rejection episodes that require treatment and have the fewest adverse effects. Finally, the use of statins has brought added benefit to immunosuppressive regimens by improving outcomes after cardiac transplantation, reportedly because of an immunomodulatory property. Promising newer immunosuppressive agents await clinical trials. This review presents an overview of the emerging data on immunosuppressive therapy for cardiac transplantation.
Nat Clin Pract Cardiovasc Med 2006 Apr
PMID:Immunosuppression for heart transplantation: where are we now? 1656 29

Vascular smooth muscle cells (VSMCs) are not terminally differentiated and, owing to their remarkable plasticity, can change to a dedifferentiated state in response to vascular injury. Our understanding of the contractility of VSMCs is mainly based on the data obtained from normal adult animals. However, to obtain a better understanding of the abnormal contractility seen in the vascular diseases such as hypertension and vasospasm superimposed on atherosclerosis, it is important to also know the contractility of proliferating dedifferentiated VSMCs. To this end, we studied the contractility of cultured VSMCs that undergo dedifferentiation similar to that induced by vascular injury. There are only a few reports in which the contractility of cultured VSMCs has been extensively studied. We established a method to investigate the contractility of the cultured VSMCs and determined that their contraction is dramatically changed to be more dependent on the Rho-Rho kinase system but less dependent on the PKC-CPI-17 (protein kinase C-potentiated protein phosphatase 1 inhibitory protein)-mediated pathway. In this review, we focus on the contractility of the cultured VSMCs as a model of the proliferating dedifferentiated VSMCs.
Trends Cardiovasc Med 2006 May
PMID:Dependence of proliferating dedifferentiated vascular smooth muscle contraction on Rho-Rho kinase system. 1671 35

Transgenic mice are often used to study the physiologic role of a known gene. The design of experiments with transgenic mice usually does not take into account strain and sex differences, at least in isolated vessels. Therefore, we have compared the contractile response of isolated aortae and isolated pulmonary arteries of male and female mice of different strains (CD1, BL6, and DBA). Contractile stimulation was achieved by depolarization due to KCl, alpha1-adrenoceptor stimulation by phenylephrine and inhibition of protein phosphatase activity by cantharidin. In isolated aorta, strain-specific differences in contractility and sex-specific differences could be observed. The concentration of phenylephrine (PE) inducing half maximal contraction (EC50) was different between aortae from DBA male mice and the other strains tested. Phasic contractions of isolated aortic rings due to PE were seen in all mice except DBA male. In isolated pulmonary arteries, strain-specific differences and sex-specific differences could be observed. The EC50-values of PE were not different between all groups. Phasic contractions due to PE were only seen in pulmonary arteries from CD1 male and BL6 female. In conclusion, strain- and sex-specific differences should be considered in selecting mice used for transgenesis or gene targeting experiments.
J Cardiovasc Pharmacol 2006 Jul
PMID:Comparison of contractile responses in isolated mouse aorta and pulmonary artery: Influence of strain and sex. 1689 10

Cardiovascular disease is the major cause of death in industrialized nations. Targeted intervention in calcineurin, a calmodulin-dependent, calcium-activated phosphatase and its substrate, nuclear factor of activated T cells (NFAT), was demonstrated to be effective in the treatment of cardiovascular diseases. Although effective in the disruption of calcineurin phosphatase activity, cyclosporin A (CsA) and FK506 also resulted in undesired side effects and toxicity, prompting the discovery of VIVIT, a novel peptide inhibitor. VIVIT selectively and potently inhibits calcineurin/NFAT interaction, but does not compromise calcineurin phosphatase activity and non-NFAT-mediated signaling. VIVIT displays a favorable therapeutic profile as a potential drug candidate and constitutes a useful tool in exploring calcineurin-NFAT functionality. This review describes the development of VIVIT peptide as a selective NFAT inhibitor and its application as a therapeutic agent in cardiovascular disorders including cardiac hypertrophy, restenosis, atherosclerosis, and angiogenesis.
Cardiovasc Drug Rev 2007
PMID:Therapeutic potential of VIVIT, a selective peptide inhibitor of nuclear factor of activated T cells, in cardiovascular disorders. 1761 39

The endothelin axis promotes vasoconstriction, suggesting that antagonists of endothelin signaling might be useful in treatment of heart failure. However, promising results from animal trials have not been recapitulated in heart failure patients. Here we review the role of major signaling pathways in the heart that are involved in cell survival initiated by ET-1. These pathways include mitogen-activated protein kinase, phosphatidyl inositol-1,4,5-triphosphate kinase (PI3K-AKT), nuclear factor-kappaB (NF-kappaB), and calcineurin signaling. A better understanding of endothelin-mediated signaling in cardiac cell survival may allow a reevaluation of endothelin receptor antagonists (ETRAs) in the treatment of heart failure.
Trends Cardiovasc Med 2008 Oct
PMID:Cardioprotective signaling by endothelin. 1923 51


<< Previous 1 2 3 4 5 Next >>