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)

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.
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PMID:Failure of calcineurin inhibitors to prevent pressure-overload left ventricular hypertrophy in rats. 1018 63

Cardiac hypertrophy is the fundamental adaptation of the adult heart to mechanical load. Recent work has shown that inhibition of calcineurin activity with cyclosporine suppresses the development of hypertrophy in calcineurin transgenic mice and in in vitro systems of neonatal rat cardiocytes stimulated with peptide growth factors. To test the hypothesis that the calcineurin signaling pathway is critical for load-induced hypertrophy in vivo, we examined the effects of cyclosporine treatment on left ventricular hypertrophy induced by experimental ascending aortic stenosis for 4 weeks in mice. Left ventricular systolic pressure was elevated to a similar level in aortic stenosis mice that were treated with cyclosporine versus no drug. Left ventricular mass and myocyte size were similar in treated and untreated aortic stenosis animals and significantly greater than control animals, showing that cyclosporine treatment does not suppress hypertrophic growth. Both treated and untreated animals showed increased left ventricular expression of the load-sensitive gene atrial natriuretic factor. Calcineurin activity was measured in the left ventricle and the spleen from control mice and aortic stenosis mice treated with cyclosporine versus no drug. Levels of calcineurin activity were similar in the spleens of control and untreated aortic stenosis mice. However, calcineurin activity was severely depressed in left ventricular tissue of untreated aortic stenosis mice compared with control mice and was further reduced by cyclosporine treatment. Thus, pathological hypertrophy and cardiac-restricted gene expression induced by pressure overload in vivo are not suppressed by treatment with cyclosporine and do not appear to depend on the elevation of left ventricular calcineurin activity.
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PMID:Pressure overload induces severe hypertrophy in mice treated with cyclosporine, an inhibitor of calcineurin. 1018 63

Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg. kg-1. d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39+/-0. 16 mg/g) than in the cyclosporine-treated banded group (3.95+/-0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02+/-0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6+/-6.1 mm Hg) and nontreatment groups (48.7+/-4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774+/-656 mm Hg/s) than in the nontreatment banded group (6604+/-516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66+/-3.0%) than in the nontreatment banded group (79+/-1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.
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PMID:Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure. 1018 63

We studied an alteration of calcineurin expression in the heart and its modification by cyclosporin A and an ACE inhibitor, temocapril, using Dahl salt-sensitive (DS) rats with hypertensive left ventricular hypertrophy (LVH) and congestive heart failure (CHF). Calcineurin protein expression in the LV myocardium was increased in the LVH stage, but then decreased during CHF transition. Chronic cyclosporin A treatment (10 mg/kg/day), which inhibits calcineurin activity, could not block the increases of LV weight and dimensions and did not improve the LV systolic function during the CHF transition. In contrast, chronic temocapril treatment (20 mg/kg/day) restored the downregulation of calcineurin expression, but progression of the hypertrophic process was inhibited. Therefore, cardiac calcineurin is increased in the hypertensive LVH and may be involved in the development of the adaptive hypertrophic process. However, calcineurin expression is downregulated during CHF transition and may no longer play a major role in the pathogenesis of myocardial hypertrophy in the failing hearts.
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PMID:Cardiac calcineurin during transition from hypertrophy to heart failure in rats. 1087 9

Calcineurin inhibitors are a mainstay of transplant immunosuppression and commonly induce hypertension. They are highly lipid soluble and penetrate vascular smooth muscle cell membranes readily. Changes in vascular tone are universally observed during administration of these agents, particularly within the kidney, leading to diminished glomerular filtration and enhanced sodium retention. Disturbances of endothelial function are prevalent in many tissues, including stimulation of endothelin and impaired nitric oxide synthesis. Multiple additional pathways produce increased vasoconstriction, leading to an increase in arterial pressure. Clinical manifestations include disturbances in circadian blood pressure patterns, left ventricular hypertrophy, and acceleration of atherosclerotic and renal injury. Rapid increases in pressure occasionally produce accelerated hypertension and microangiopathic tissue damage. Principles of therapy require recognition of hazards of changing arterial pressures during calcineurin use and preferential use of vasodilating drugs, particularly dihydropyridine calcium channel blocking agents. Attention must be paid to interactions between antihypertensive agents and calcineurin inhibitor blood levels.
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PMID:Posttransplantation hypertension related to calcineurin inhibitors. 1098 50

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)), when treated with calcineurin inhibitors or a K(+)-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca(2+) concentrations in wild-type cardiac myocytes; alphaMHC(403/+) myocytes failed to respond. Pretreatment with a Ca(2+)-channel antagonist abrogated diastolic Ca(2+) changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alphaMHC(403/+) mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca(2+) responses that initiate a hypertrophic response. These data define an important Ca(2+)-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.
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PMID:An abnormal Ca(2+) response in mutant sarcomere protein-mediated familial hypertrophic cardiomyopathy. 1112 Jul 49

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.
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PMID:Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. 1168 89

Calcineurin is a Ca(2+)/calmodulin-activated protein phosphatase that transduces hypertrophic stimuli to regulate transcriptional control of myocyte transformation. It is not known whether overexpression of MCIP1, a recently described endogenous inhibitor of calcineurin, impacts the hypertrophic response to pathophysiologically relevant pressure overload. Further, the functional consequences of calcineurin inhibition by MCIP1 under conditions of hemodynamic stress are unknown. Transgenic mice expressing a human cDNA encoding hMCIP1 in the myocardium were subjected to thoracic aortic banding. Transgenic mice and wild type littermates tolerated pressure overload equally well. Wild type mice developed left ventricular hypertrophy, but the hypertrophic response in transgenics was significantly blunted. An isoform of MCIP1 transcript was up-regulated by pressure stress, whereas MCIP2 transcript was not. Expression patterns of fetal genes were differentially regulated in banded MCIP1 hearts compared with wild type. Echocardiography performed at 3 weeks and 3 months revealed preservation of both left ventricular size and systolic function in banded MCIP1 mice despite the attenuated hypertrophic response. These data demonstrate attenuation of hypertrophic transformation when calcineurin is inhibited by MCIP1. Further, these data suggest that activation of hypertrophic marker genes may not be directly dependent on calcineurin activity. Finally, they demonstrate that ventricular performance is preserved despite attenuation of compensatory hypertrophy.
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PMID:Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. 1178 44

In the past 2 years, an emerging body of research has focused on a novel transcriptional pathway involved in the cardiac hypertrophic response. Ever since its introduction, the significance of the calcineurin-NFAT module has been subject of controversy. The aim of this review is to provide both an update on the current status of knowledge and discuss the remaining issues regarding the involvement of calcineurin in hypertrophic heart disease. To this end, the molecular biology of calcineurin and its direct downstream transcriptional effector NFAT are discussed in the context of the genetic studies that established the existence of this signaling paradigm in the heart. The pharmacological mode-of-action and specificity of the calcineurin inhibitors cyclosporine A (CsA) and FK506 is discussed, as well as their inherent limitations to study the biology of calcineurin. A critical interpretation is given on studies aimed at analyzing the role of calcineurin in cardiac hypertrophy using systemic immunosuppression. To eliminate the controversy surrounding CsA/FK506 usage, recent studies employed genetic inhibitory strategies for calcineurin, which confirm the pivotal role for this signal transduction pathway in the ventricular hypertrophy response. Finally, unresolved issues concerning the role of calcineurin in cardiac pathobiology are discussed based upon the information available, including its controversial role in cardiomyocyte viability, the reciprocal relationship between myocyte Ca(2+) homeostasis and calcineurin activity and the relative importance of calcineurin in relation to other hypertrophic signaling cascades.
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PMID:Calcineurin and hypertrophic heart disease: novel insights and remaining questions. 1192 91

Decreased nitric oxide synthase (NOS) activity induces left ventricular hypertrophy (LVH), but the transcriptional pathways mediating this effect are unknown. We hypothesized that specific NOS isoform deletion (NOS3 or NOS1) would activate different transcriptional programs in LVH. We analyzed cardiac expression profiles (Affymetrix MG-U74A) from NOS-/- mice using robust multi-array average (RMA). Of 12,422 genes analyzed, 47 genes were differentially expressed in NOS3-/- and 67 in NOS1(-/-) hearts compared with wild type (WT). Only 16 showed similar changes in both NOS-/- strains, most notably decreased heat-shock proteins (HSP10, 40, 70, 86, 105). Hypertrophied NOS1-/- hearts had unique features, including decreased myocyte-enriched calcineurin interacting protein and paradoxical downregulation of fetal isoforms (alpha-skeletal actin and brain natriuretic peptide). Cluster analyses demonstrated that NOS1 deletion caused more pronounced changes in the myocardial transcriptome than did NOS3 deletion, despite similar cardiac phenotypes. These findings suggest that the transcriptional basis for LVH varies depending on the inciting biochemical stimulus. In addition, NOS isoforms appear to play distinct roles in modulating cardiac structure.
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PMID:Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy. 1270 11


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