Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biomechanical environment to which cells are exposed is important to their normal growth, development, interaction, and function. Accordingly, there has been much interest in studying the role of biomechanical forces in cell biology and pathophysiology. This has led to the introduction and even commercialization of many experimental devices. Many of the early devices were limited by the heterogeneity of deformation of cells cultivated in different locations of the culture plate membranes and were also attached with complicated technical/electronic efforts resulting in a restriction of the reproducibility of these devices. The objective of this study was to design and build a simple device to allow the application of dose-dependent homogeneous equibiaxial static stretch to cells cultured on flexible silicone membranes to investigate biological and biomedical questions. In addition, cultured neonatal rat atrial cardiomyocytes were stretched with the proposed device with different strain gradients. For the first time with this study we could demonstrate that stretch up to 21% caused dose-dependent changes in biological markers such as the calcineurin activity, modulatory calcineurin-interacting protein-1, voltage-gated potassium channel isoform 4.2, and voltage-gated K(+) channel-interacting proteins-2 gene expression and transient outward potassium current densities but not the protein-to-DNA ratio and atrial natriuretic peptide mRNA. With both markers mentioned last, dose-dependent stretch alterations could only be achieved with stretch up to 13%. The simple and low-cost device presented here might be applied to a wide range of experimental settings in different fields of research.
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PMID:A simple device to apply equibiaxial strain to cells cultured on flexible membranes. 1796 85

In the heart, cytosolic Ca(2+) signals are well-characterized events that participate in the activation of cell contraction. In contrast, nuclear Ca(2+) contribution to cardiomyocyte function remains elusive. Here, we examined functional consequences of buffering nuclear Ca(2+) in neonatal cardiomyocytes. We report that cardiomyocytes contain a nucleoplasmic reticulum, which expresses both ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (InsP(3)R), providing a possible way for active regulation of nuclear Ca(2+). Adenovirus constructs encoding the Ca(2+) buffer protein parvalbumin were targeted to the nucleus with a nuclear localization signal (Ad-PV-NLS) or to the cytoplasm with a nuclear exclusion signal (Ad-PV-NES). A decrease in the amplitude of global Ca(2+) transients and RyR-II expression, as well as an increase in cell beating rate were observed in Ad-PV-NES and Ad-PV-NLS cells. When nuclear Ca(2+) buffering was imposed nuclear enlargement, increased calcineurin expression, NFAT translocation to the nucleus and subcellular redistribution of atrial natriuretic peptide were observed. Furthermore, prolongation of action potential duration occurred in adult ventricular myocytes. These results suggest that nuclear Ca(2+) levels underlie the regulation of specific protein targets and thereby modulate cardiomyocyte function. The local nuclear Ca(2+) signaling and the structures that control it constitute a novel regulatory motif in the heart.
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PMID:Nuclear Ca2+ regulates cardiomyocyte function. 1820 61

We tested the hypothesis that female and male mice differ in terms of cardiac hypertrophy after deoxycorticosterone acetate (DOCA)+salt hypertension (uninephrectomy and 1% saline in drinking water) and focused on calcineurin signaling. We excluded confounding effects of blood pressure elevation or sex-related blood pressure differences by treating DOCA-salt mice with hydralazine (250 mg/L in drinking water). We found that directly measured mean arterial blood pressure was lowered to control values with hydralazine and corroborated this finding in separate mouse groups with radiotelemetry. Male mice were more responsive to DOCA-salt-related effects. They developed more left ventricular hypertrophy and more renal hypertrophy after 6 weeks of DOCA-salt+hydralazine compared with female mice. In hearts, transcripts for calcineurin Abeta and for myocyte-enriched calcineurin interacting protein 1 were upregulated in male but not in female mice. Enhanced activity of calcineurin Abeta, as indicated by diminished phosphorylation of NFATc2 in male mice, accounted for this sex-specific difference. Stretch-related, inflammatory, and profibrotic responses were also accentuated in male mice, as shown by higher transcript levels of atrial natriuretic peptide, monocyte chemoattractant protein-1, and transforming growth factor-beta. Our results support sex-specific regulation of the calcineurin pathway in response to largely blood pressure-independent mineralocorticoid action. We suggest that sex-specific calcineurin activation determines the maladaptive cardiac and renal hypertrophic responses and accompanying organ injury in male mice.
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PMID:Deoxycorticosterone acetate-salt mice exhibit blood pressure-independent sexual dimorphism. 1825 6

Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to cause the cardiac hypertrophy. In the present study, we treated H9c2 myocardiac cells with LPS to explore whether LPS causes cardiac hypertrophy, and to identify the precise molecular and cellular mechanisms behind hypertrophic responses. Here we show that LPS challenge induces pathological hypertrophic responses such as the increase in cell size, the reorganization of actin filaments, and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in H9c2 cells. LPS treatment significantly promotes the activation of GATA-4 and the nuclear translocation of NFAT-3, which act as transcription factors mediating the development of cardiac hypertrophy. After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), FK506 (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), LPS-induced hypertrophic characteristic features, such as increases in cell size, actin fibers, and levels of ANP and BNP, and the nuclear localization of NFAT-3 are markedly inhibited only by calcineurin inhibitors, CsA and FK506. Collectively, these results suggest that LPS leads to myocardiac hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 cells. Our findings further provide a link between the LPS-induced inflammatory response and the calcineurin/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy.
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PMID:Lipopolysaccharide induces cellular hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 myocardiac cells. 1839 69

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.
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PMID:Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy. 1846 52

Ginsenosides have been reported to release nitric oxide (NO) and decrease intracellular free Ca(2+) in cardiovascular system, which play important roles in antihypertrophic effect. This study investigated the potential inhibitory effect of total ginsenosides (TG) on right ventricular hypertrophy induced by monocrotaline (MCT, 60 mg/kg/d) and examined the possible antihypertrophic mechanism in male Sprague Dawley rats. MCT-intoxicated animals were treated with TG (20, 40, 60 mg/kg/d) for 18 d. TG treatment ameliorated MCT-induced elevations in right ventricular peak systolic pressure, right ventricular hypertrophy and the expression of atrial natriuretic peptide; N(G)-nitro-L-arginine-methyl ester (L-NAME), an NO synthase (NOS) inhibitor, had no influence on these inhibitory effects of TG 40 mg/kg/d, and TG at this dose had no any effect on the eNOS mRNA expression, suggesting the limited rule of NO in TG's effects. To further examine the mechanisms of the protection, the expression of calcineurin and its catalytic subunit CnA, as well as extracellular signal-regulated kinase-1 (ERK-1) and mitogen-activated protein kinase (MAPK) Phosphatase-1 (MKP-1) was examined. TG treatment significantly suppressed MCT-induced elevations of these signaling pathways in a dose-dependent manner. In summary, TG is effective in protecting against MCT-induced right ventricle hypertrophy, possibly through lowering pulmonary hypertension. Multiple molecular mechanisms appeared to be involved in this protection, such as the suppression of MCT-activated calcineurin and ERK signaling pathways.
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PMID:Total ginsenosides inhibit the right ventricular hypertrophy induced by monocrotaline in rats. 1867 84

Ginsenoside Rg(1) (Rg(1)), one of the active components of Panax ginseng, has been reported to inhibit proliferation of vascular smooth muscle cells induced by tumor necrosis factor-alpha. This study aims to investigate whether Rg(1) has protective effect on rat left ventricular hypertrophy and to probe its protective mechanisms. The rat left ventricular hypertrophy was induced by abdominal aorta coarctation and Rg(1) (3.75, 7.5 and 15 mg/kg/day) was given the day after surgery for 21 consecutive days. The left ventricular hypertrophy induced by abdominal aorta coarctation was evidenced by histopathology, electromicroscopy, and by determining the elevated left ventricular weight and the expression of atrial natriuretic peptide. Rg(1) significantly ameliorated left ventricular hypertrophy induced by abdominal aorta coarctation in a dose-dependent manner. To examine the mechanism of protection, the expressions of calcineurin, CnA (the catalytic subunit of calcineurin), extracellular signal-regulated kinase-1, and mitogen-activated protein (MAP) kinase phosphatase-1 were determined at the transcript and protein levels. The abdominal aorta coarctation induced increases in calcineurin, CnA, and extracellular signal-regulated kinase-1 expressions were suppressed, but the expression of MAP kinase phosphatase-1 was increased by Rg(1). These results demonstrate that Rg(1) alleviates left ventricular hypertrophy induced by abdominal aorta coarctation, and the protection appears to be due, at least in part, to its inhibitory effects on calcineurin and MAP kinase signaling pathways.
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PMID:Ginsenoside Rg(1) inhibits rat left ventricular hypertrophy induced by abdominal aorta coarctation: involvement of calcineurin and mitogen-activated protein kinase signalings. 1934 83

Calcineurin, a serine/threonine phosphatase, plays a crucial role in the development of myocardial hypertrophy. Calcineurin is a cytosolic phosphatase that dephosphorylates the nuclear factor of activated T cells (NFAT), a transcription factor. Until now, it has been postulated that dephosphorylated NFAT is shuttled into the nucleus. Recent evidence demonstrates that not only NFAT, but also calcineurin, is localized in the nucleus. Once calcineurin and NFAT enter the nucleus of cardiomyocytes, transcription of genes that are characteristic for myocardial hypertrophy (e.g., brain natriuretic peptide and atrial natriuretic peptide) occurs. Although the exact nuclear function of calcineurin remains unclear, its co-existence with NFAT is important for the full transcriptional activity of the calcineurin/NFAT signaling cascade. The principal effect of nuclear calcineurin is likely the prolonged nuclear retention period of NFAT. Potential effects of nuclear calcineurin include an antagonistic function to glycogen synthase kinase 3beta, which phosphorylates NFAT for its export out of the nucleus, or direct antagonization of the export of NFAT, catalyzed by the chromosome region maintenance 1, which would leave NFAT nuclear. The nuclear localization sequence (NLS) region at the amino acid sequence from position 172 to 183 of calcineurin Abeta is essential for shuttling calcineurin into the nucleus by importinbeta(1). A synthetic import blocking peptide (IBP) that mimics the nuclear localization sequence of calcineurin was generated. The NLS analog on IBP saturates the calcineurin binding site of importinbeta(1). This prevents the binding of calcineurin to importin and inhibits the nuclear shuttling of calcineurin. Inhibition of the calcineurin/importinbeta(1) interaction by competing synthetic peptides represents a new approach to the inhibition of the development of myocardial hypertrophy.
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PMID:New approach to prevent myocardial hypertrophy: the import blocking peptide. 1980 10

LIM domain proteins are important regulators in cell growth, cell fate determination, cell differentiation, and remodeling of the cell cytoskeleton. LIM and cysteine-rich domains 1 (Lmcd1) is a novel protein that contain 2 LIM domains with regular spacing in the carboxy-terminal region. However, its roles in cardiac growth remain unknown. Here, we investigated whether Lmcd1 regulates cardiac hypertrophy in vitro and in vivo and elucidated the underlying molecular mechanisms. We used primary cultured cardiac myocytes and cardiac-specific Lmcd1 transgenic mice. In wild-type mice subjected to the aortic banding, cardiac hypertrophy was evident at 8 weeks. In transgenic mice, however, cardiac hypertrophy was significantly greater than that in wild-type mice, as estimated by heart weight:body weight ratio, cardiomyocyte area, and echocardiographic measurements, as well as cardiac atrial natriuretic peptide and B-type natriuretic peptide mRNA and protein levels. Our results further showed that cardiac fibrosis observed in wild-type aortic banding mice was augmented in transgenic aortic banding mice. Importantly, calcineurin activity and nuclear factor of activated T cells activation level were increased more in transgenic mice than those in wild-type mice after 8-week aortic banding. In vitro experiments in cardiac myocytes further revealed that angiotensin II-induced calcineurin activity and nuclear factor of activated T cells activation were enhanced by overexpression but blunted by downregulation of Lmcd1. In conclusion, our results suggest that Lmcd1 plays a critical role in the development of cardiac hypertrophy via activation of calcineurin/nuclear factor of activated T cells signaling pathway.
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PMID:LIM and cysteine-rich domains 1 regulates cardiac hypertrophy by targeting calcineurin/nuclear factor of activated T cells signaling. 2002 62

Scutellarin is a flavonoid extracted from a traditional Chinese herb, Erigeron breviscapus Hand Mazz, which has been broadly used in treating various cardiovascular diseases. In this study, we investigated its effect on cardiac hypertrophy and the underlying mechanism. Both in vitro and in vivo cardiac hypertrophy models were employed to explore the anti-hypertrophic action of scutellarin. We found that scutellarin significantly suppressed the hypertrophic growth of neonatal cardiac myocytes exposed to phenylephrine (PE) and mouse heart subjected to pressure overload induced by aortic banding, accompanied with the decreased expression of hypertrophic markers beta-myosin heavy chain and atrial natriuretic peptide. We then measured the change of free intracellular calcium using laser scanning confocal microscope. We found that scutellarin alleviated the increment of free intracellular calcium during cardiac hypertrophy either induced by PE or aortic banding. The expression of calcium downstream effectors calcineurin and phosphorylated calmodulin kinase II (CaMKII) were significantly suppressed by scutellarin. Our study indicated that scutellarin exerts its anti-hypertrophic activity via suppressing the Ca(2+)-mediated calcineurin and CaMKII pathways, which supports the observation that clinical application of scutellarin is beneficial for cardiovascular disease patients.
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PMID:Scutellarin exerts its anti-hypertrophic effects via suppressing the Ca2+-mediated calcineurin and CaMKII signaling pathways. 2005 60


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