tacrolimus and Cardiomegaly

Topics: Animals; Calcineurin; Cardiomegaly; Cyclosporine; Gene Expression; Humans; Immunosuppressive Agents; NFATC Transcription Factors; Signal Transduction; Tacrolimus

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.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cyclosporine; Heart Failure; Humans; Signal Transduction; Tacrolimus

Topics: A Kinase Anchor Proteins; Adaptor Proteins, Signal Transducing; Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Carrier Proteins; Cyclosporine; DNA-Binding Proteins; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Muscle Proteins; Phosphoproteins; Tacrolimus

In response to increased ventricular wall tension or neurohumoral stimuli, the myocardium undergoes an adaptive hypertrophy response that temporarily augments pump function. Although initially beneficial, sustained cardiac hypertrophy can lead to decompensation and cardiomyopathy. Recent studies have focused on characterizing the molecular mechanisms that underlie cardiac hypertrophy. An increasing number of signal transduction pathways have been identified as important regulators of the hypertrophic response, including the low-molecular weight GTPases (Ras, RhoA, and Rac), mitogen-activated protein kinases, protein kinase C, and calcineurin. This review will discuss an emerging body of evidence that implicates the calcium-calmodulin-activated protein phosphatase calcineurin as a physiological regulator of the cardiac hypertrophic response. Although the sufficiency of calcineurin to promote cardiomyocyte hypertrophy in vivo and in vitro is established, its overall necessity as a hypertrophic mediator is currently an area of ongoing debate. The use of the calcineurin-inhibitory agents cyclosporine A and FK506 have suggested a necessary role for calcineurin in many, but not all, animal models of hypertrophy or cardiomyopathy. The evidence implicating a role for calcineurin signaling in the heart will be weighed against a growing body of literature suggesting necessary roles for a diverse array of intracellular signaling pathways, highlighting the multifactorial nature of the hypertrophic program.

Topics: Amino Acid Sequence; Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Cell Nucleus; Cyclosporine; Cytoplasm; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Immunosuppressive Agents; Mice; Mice, Transgenic; Models, Animal; Molecular Sequence Data; NFATC Transcription Factors; Nuclear Proteins; Signal Transduction; T-Lymphocytes; Tacrolimus; Transcription Factors; Transcription, Genetic

Topics: Amino Acid Sequence; Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Calcium Signaling; Cardiomegaly; Cyclosporine; DNA-Binding Proteins; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Immunosuppressive Agents; Mice; Models, Biological; Molecular Sequence Data; Multigene Family; Myocardium; NFATC Transcription Factors; Nuclear Proteins; Organ Specificity; Protein Isoforms; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Tacrolimus; Transcription Factors; Transfection

A-kinase anchoring protein 5 (AKAP5) is involved in ventricular remodeling in rats with heart failure after myocardial infarction; however, the specific mechanism is not clear. This study investigated whether AKAP5 anchors calcineurin (CaN) to regulate the remodeling of H9c2 cardiomyocytes.. H9c2 cells were subjected to hypoxia stress for 3 h and reoxygenation for 24 h to create a hypoxia-reoxygenation (H/R) model. These cells were divided into three groups: H/R (model), empty vector +H/R (NC), and siRNA-AKAP5+H/R (siRNA-AKAP5) groups. The non-H/R H9c2 cells were used as normal controls. Western blotting was used to detect cardiac hypertrophy-related protein expression in the cells, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta myosin heavy chain (β-MHC), and phosphorylated nuclear factor of activated T-cell 3 (p-NFATc3). Phalloidin staining was used to label the cytoskeleton and the cell area in different groups was measured. Immunofluorescence staining and coimmunoprecipitation were used to study the relationship between AKAP5 and CaN. H9c2 cells pretreated with the CaN inhibitor FK506 were used to further verify the relationship between AKAP5 and CaN.. In the siRNA-AKAP5+H/R group, the expression level of cardiac hypertrophy-related proteins (ANP, BNP, and β-MHC) and CaN and the area of cardiomyocytes were significantly increased, while the p-NFATc3/NFATc3 ratio was decreased in H9c2H/R cells. AKAP5 and CaN proteins were colocalized and interacted in the cells. The CaN inhibitor significantly suppressed the expression of CaN, increased the p-NFATc3/NFATc3 ratio, and reduced the expression levels of ANP, BNP, and β-MHC proteins in the cells with low AKAP5 expression.. AKAP5 downregulation aggravated the remodeling of cardiomyocytes after H/R. AKAP5 may anchor CaN to form a complex, which in turn activates NFATc3 dephosphorylation and expression of hypertrophy-related proteins.

Topics: A Kinase Anchor Proteins; Animals; Atrial Natriuretic Factor; Calcineurin; Cardiomegaly; Hypoxia; Myocytes, Cardiac; Myosin Heavy Chains; Natriuretic Peptide, Brain; Phalloidine; Rats; RNA, Small Interfering; Tacrolimus

Heart failure is a leading cause of morbidity and mortality in Western society. The cardiovascular transcription factor CHF1/Hey2 has been linked to experimental heart failure in mice, but the mechanisms by which it regulates myocardial function remain incompletely understood. The objective of this study was to determine how CHF1/Hey2 affects development of heart failure through examination of contractility in a myocardial knockout mouse model. We generated myocardial-specific knockout mice. At baseline, cardiac function was normal, but, after aortic banding, the conditional knockout mice demonstrated a greater increase in ventricular weight-to-body weight ratio compared with control mice (5.526 vs. 4.664 mg/g) and a significantly decreased ejection fraction (47.8 vs. 72.0% control). Isolated cardiac myocytes from these mice showed decreased calcium transients and fractional shortening after electrical stimulation. To determine the molecular basis for these alterations in excitation-contraction coupling, we first measured total sarcoplasmic reticulum calcium stores and calcium-dependent force generation in isolated muscle fibers, which were normal, suggesting a defect in calcium cycling. Analysis of gene expression demonstrated normal expression of most genes known to be involved in myocardial calcium cycling, with the exception of the ryanodine receptor binding protein FKBP12.6, which was expressed at increased levels in the conditional knockout hearts. Treatment of the isolated knockout myocytes with FK506, which inhibits the association of FKBP12.6 with the ryanodine receptor, restored contractile function. These findings demonstrate that conditional deletion of CHF1/Hey2 in the myocardium leads to abnormalities in calcium handling mediated by FKBP12.6 that predispose to pressure overload-induced heart failure.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium; Cardiomegaly; Cells, Cultured; Disease Models, Animal; Heart Conduction System; Heart Failure; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Contraction; Myocytes, Cardiac; Repressor Proteins; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Stroke Volume; Tacrolimus; Tacrolimus Binding Proteins

Leptin, a product of the obesity gene, has been shown to produce cardiac hypertrophy. Although leptin's mechanism of action is poorly understood activation of the RhoA/ROCK pathway has been proposed as a contributing mechanism. The Ca(2+)-dependent phosphatase calcineurin plays a critical role in the hypertrophic program although it is not known whether leptin can activate this signaling pathway or whether there is a relationship between RhoA activation and calcineurin. Accordingly, we determined the effect of leptin on calcineurin activation and assessed the possible role of RhoA. Experiments were performed using cultured neonatal rat ventricular myocytes exposed to 50 ng/ml leptin for 24h which resulted in a robust hypertrophic response. Moreover, leptin significantly increased intracellular Ca(2+) and Na(+) concentrations which was associated with significantly reduced activity of the 3Na(+)-2K(+)ATPase. The hypertrophic response to leptin were completely abrogated by both C3 exoenzyme (C3), a RhoA inhibitor as well as the reverse mode 3Na(+)-1Ca(2+) exchange inhibitor KB-R7943 ((2-[2-[4-(4-nitrobenzyloxy)phenyl] ethyl]isothiourea methanesulfonate), however only the effect of the latter was associated with attenuation of intracellular Ca(2+) concentrations whereas Ca(2+) concentrations were unaffected by C3. Similarly, C3 and KB-R7943 significantly attenuated early leptin-induced increase in calcineurin activity as well as the increase in nuclear translocation of the transcriptional factor nuclear factor of activated T cells. The hypertrophic response to leptin was also associated with increased p38 and ERK1/2 MAPK phosphorylation and increased p38, but not ERK1/2, translocation into nuclei. Both p38 responses as well as hypertrophy were abrogated by KB-R7943 as well as the calcineurin inhibitor FK-506 although ERK1/2 phosphorylation was unaffected. Our study therefore demonstrates a critical role for the calcineurin pathway in mediating leptin-induced hypertrophy. Moreover, we report a novel RhoA-dependent leptin-induced calcineurin activation which acts independently of changes in intracellular Ca(2+) concentrations.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiomegaly; Cell Nucleus; Cells, Cultured; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocytes, Cardiac; NFATC Transcription Factors; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; rhoA GTP-Binding Protein; Signal Transduction; Sodium-Potassium-Exchanging ATPase; Tacrolimus; Thiourea; Translocation, Genetic

Common cardiovascular diseases such as hypertension and myocardial infarction require that myocytes develop greater than normal force to maintain cardiac pump function. This requires increases in [Ca(2+)]. These diseases induce cardiac hypertrophy and increases in [Ca(2+)] are known to be an essential proximal signal for activation of hypertrophic genes. However, the source of "hypertrophic" [Ca(2+)] is not known and is the topic of this study. The role of Ca(2+) influx through L-type Ca(2+) channels (LTCC), T-type Ca(2+) channels (TTCC) and transient receptor potential (TRP) channels on the activation of calcineurin (Cn)-nuclear factor of activated T cells (NFAT) signaling and myocyte hypertrophy was studied. Neonatal rat ventricular myocytes (NRVMs) and adult feline ventricular myocytes (AFVMs) were infected with an adenovirus containing NFAT-GFP, to determine factors that could induce NFAT nuclear translocation. Four millimolar Ca(2+) or pacing induced NFAT nuclear translocation. This effect was blocked by Cn inhibitors. In NRVMs Nifedipine (Nif, LTCC antagonist) blocked high Ca(2+)-induced NFAT nuclear translocation while SKF-96365 (TRP channel antagonist) and Nickel (Ni, TTCC antagonist) were less effective. The relative potency of these antagonists against Ca(2+) induced NFAT nuclear translocation (Nif>SKF-96365>Ni) was similar to their effects on Ca(2+) transients and the LTCC current. Infection of NRVM with viruses containing TRP channels also activated NFAT-GFP nuclear translocation and caused myocyte hypertrophy. TRP effects were reduced by SKF-96365, but were more effectively antagonized by Nif. These experiments suggest that Ca(2+) influx through LTCCs is the primary source of Ca(2+) to activate Cn-NFAT signaling in NRVMs and AFVMs. While TRP channels cause hypertrophy, they appear to do so through a mechanism involving Ca(2+) entry via LTCCs.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Calcium Signaling; Cardiomegaly; Cell Nucleus; Cells, Cultured; Heart Ventricles; Imidazoles; Myocytes, Cardiac; NFATC Transcription Factors; Nickel; Nifedipine; Protein Transport; Rats; Rats, Sprague-Dawley; Tacrolimus; TRPC Cation Channels; Ventricular Remodeling

Mechanical stress can induce cardiac hypertrophy through angiotensin II (AngII) type 1 (AT(1)) receptor independently of AngII, however, the intracellular mechanisms remain largely indeterminate. Since calcineurin, a Ca(2+)-dependent phosphatase, plays a critical role in pressure overload-induced cardiac hypertrophy, we therefore, asked whether calcineurin is involved in the AT(1) receptor-mediated but AngII-independent cardiac hypertrophy. Mechanical stretch failed to elicit hypertrophic responses in COS7 cells co-transfected with plasmid of AT(1) receptor and siRNA of calcineurin. Mechanical stresses for 2weeks in vivo and for 24h in vitro significantly induced upregulation of calcineurin expression and hypertrophic responses, such as the increases in cardiomyocytes size and specific gene expressions, in cardiomyocytes of angiotensinogen gene knockout (ATG(-/-)) mice, both of which were significantly suppressed by a specific calcineurin inhibitor FK506, suggesting a critical role of calcineurin in mechanical stress-induced cardiac hypertrophy in the ATG(-/-) mice. Furthermore, an AT(1) receptor blocker Losartan not only attenuated cardiac hypertrophy but also abrogated upregulation of cardiac calcineurin expression induced by mechanical stresses in the AngII-lacking mice, indicating that calcineurin expression is regulated by AT(1) receptor without the involvement of AngII after mechanical stress. These findings collectively suggest that mechanical stress-evoked but AngII-independent activation of AT(1) receptor induces cardiac hypertrophy through calcineurin pathway.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Chlorocebus aethiops; COS Cells; Losartan; Mice; Mice, Mutant Strains; Receptor, Angiotensin, Type 1; Stress, Mechanical; Tacrolimus

Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement.

Topics: Adolescent; Biopsy; Cardiomegaly; Cardiomyopathy, Dilated; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Tacrolimus; Treatment Outcome

The calcium/calmodulin-dependent phosphatase calcineurin has been shown to be both necessary and sufficient to induce cardiac hypertrophy in vivo and in vitro. Treatment with the antineoplastic agent doxorubicin (DOX) was shown to activate calcineurin signaling in H9c2 rat cardiac muscle cells; however, the effect of this activation on hypertrophy was not investigated. Therefore, the present study was undertaken to examine the involvement of calcineurin activation in DOX-induced cardiac cell hypertrophy. H9c2 cells were treated with 1 microM DOX for 2 h following pretreatment with and in the presence of calcineurin inhibitors cyclosporine A (CsA) or FK506 (tacrolimus). Subsequent analysis of calcineurin signaling and cellular hypertrophy was performed 8 to 48 h after the treatment. DOX treatment activated calcineurin signaling and resulted in cellular hypertrophy as assessed by an increase in cell volume and protein content per cell. Inhibition of calcineurin with CsA or FK506 blocked DOX-induced calcineurin signaling. However, this inhibition did not prevent the DOX-induced hypertrophic response in H9c2 cells. Further evaluation of the possible signaling pathways involved in DOX-induced H9c2 cellular hypertrophy revealed that DOX treatment resulted in phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, the DOX-induced hypertrophic response was blunted by LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], a specific inhibitor for PI3K. These results demonstrate that, although calcineurin is activated by DOX treatment, it is not necessary for DOX-induced hypertrophy in H9c2 cells. Rather, the PI3K-Akt signaling pathway seems to be more critically involved in DOX-induced hypertrophy.

Topics: Animals; Calcineurin; Cardiomegaly; Cell Line; Cyclosporine; Dose-Response Relationship, Drug; Doxorubicin; Enzyme Activation; Myocytes, Cardiac; NFATC Transcription Factors; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; Tacrolimus

The cardiac Na(+)/Ca(2+) exchanger (NCX1) is the predominant mechanism for the extrusion of Ca(2+) from beating cardiomyocytes. The role of protein phosphorylation in the regulation of NCX1 function in normal and diseased hearts remains unclear. In our search for proteins that interact with NCX1 using a yeast two-hybrid screen, we found that the C terminus of calcineurin Abeta, containing the autoinhibitory domain, binds to the beta1 repeat of the central cytoplasmic loop of NCX1 that presumably constitutes part of the allosteric Ca(2+) regulatory site. The association of NCX1 with calcineurin was significantly increased in the BIO14.6 cardiomyopathic hamster heart compared with that in the normal control. In hypertrophic neonatal rat cardiomyocytes subjected to chronic phenylephrine treatment, we observed a marked depression of NCX activity measured as the rate of Na(+)(i)-dependent (45)Ca(2+) uptake or the rate of Na(+)(o)-dependent (45)Ca(2+) efflux. Depressed NCX activity was partially and independently reversed by the acute inhibition of calcineurin and protein kinase C activities with little effect on myocyte hypertrophic phenotypes. Studies of NCX1 deletion mutants expressed in CCL39 cells were consistent with the view that the beta1 repeat is required for the action of endogenous calcineurin and that the large cytoplasmic loop may be required to maintain the interaction of the enzyme with its substrate. Our data suggest that NCX1 is a novel regulatory target for calcineurin and that depressed NCX activity might contribute to the etiology of in vivo cardiac hypertrophy and dysfunction occurring under conditions in which both calcineurin and protein kinase C are chronically activated.

Topics: Animals; Binding Sites; Calcineurin; Calcium; Cardiomegaly; Cells, Cultured; Cricetinae; Dogs; Female; Heart; Humans; Ion Transport; Male; Mutation; Myocytes, Cardiac; Phenylephrine; Protein Binding; Rats; Sodium; Sodium-Calcium Exchanger; Tacrolimus; Tetradecanoylphorbol Acetate

Magnesium deficiency promotes vasoconstriction and myocardial damage. Recent studies provide evidence that Ang II mobilizes intracellular Mg through AT1 receptor-mediated pathways. We tested the hypothesis of whether magnesium supplementation prevents Ang II-induced myocardial damage and induction of the profibrotic connective tissue growth factor (CTGF).. Four-week-old double transgenic rats harboring human renin and angiotensinogen genes (dTGR) were given dietary magnesium supplementation (0.6%) for 3 weeks. Control dTGR and normotensive Sprague-Dawley (SD) rats received normal diet (Mg 0.2%). Histopathological, immunohistochemical and mRNA analysis were used to detect the treatment-related effects of dietary magnesium in dTGR.. Magnesium (Mg) supplementation decreased blood pressure, ameliorated cardiac hypertrophy, protected against the development of Ang II-induced myocardial damage and increased serum ionized Mg2+ concentration (all variables P < 0.05). There was no difference in serum ionized Mg2+ concentration between dTGR and SD rats. Myocardial connective tissue growth factor (CTGF) mRNA and protein expressions were increased by 300% in dTGR (P < 0.05), especially in areas with myocardial infarctions and vascular inflammation. Magnesium supplementation prevented Ang II-induced myocardial CTGF overexpression (P < 0.05). Magnesium supplementation also improved the therapeutic effects of the calcineurin inhibitor tacrolimus, which produced marked hypomagnesemia when given as monotherapy.. Our findings suggest a salutary effect for magnesium supplementation in the treatment of Ang II-induced myocardial complications.

Topics: Angiotensin II; Angiotensinogen; Animals; Animals, Genetically Modified; Blood Pressure; Cardiomegaly; Connective Tissue Growth Factor; Dietary Supplements; Fibrosis; Humans; Immediate-Early Proteins; Immunosuppressive Agents; Intercellular Signaling Peptides and Proteins; Magnesium; Male; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tacrolimus

Although disruption of guanylyl cyclase (GC) A, a natriuretic peptide receptor, induces cardiac hypertrophy and fibrosis, the molecular mechanism underlying these effects are not well understood. In this study, we examined the role of calcineurin, a calcium-dependent phosphatase, in cardiac remodeling in GCA-knockout (GCA-KO) mice.. At 14 weeks of age, calcineurin activity, nuclear translocation of nuclear factor of activated T cells c3 (NFATc3), and modulatory calcineurin-interacting protein 1 (MCIP1) gene expressions were increased in the hearts of GCA-KO mice compared with wild-type (WT) mice. Blockade of calcineurin activation by FK506 (6 mg/kg body weight administered subcutaneously once a day from 10 to 14 weeks of age) significantly decreased the heart-to-body weight ratio, cardiomyocyte size, and collagen volume fraction in GCA-KO mice, whereas FK506 did not affect these parameters in WT mice. Overexpression of atrial and brain natriuretic peptides, collagen, and fibronectin mRNAs in GCA-KO mice was also attenuated by FK506. Electrophoretic mobility shift assays demonstrated that GATA4 DNA-binding activity was increased in GCA-KO mice, and this increase was inhibited by calcineurin blockade. In neonatal cultured cardiac myocytes, inhibition of GCA by HS142-1 (100 microg/mL) increased basal and phenylephrine (10(-6) mol/L)-stimulated calcineurin activity, nuclear translocation of NFATc3, and MCIP1 mRNA expression. In contrast, activation of GCA by atrial natriuretic peptide (10(-6) mol/L) inhibited phenylephrine (10(-6) mol/L)-stimulated nuclear translocation of NFATc3.. These results suggest that activation of cardiac GCA by locally secreted natriuretic peptides protects the heart from excessive cardiac remodeling by inhibiting the calcineurin-NFAT pathway.

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; DNA-Binding Proteins; Enzyme Activation; Fibrosis; Gene Expression Regulation; Guanylate Cyclase; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Muscle Proteins; Myocardium; Natriuretic Peptide, Brain; NFATC Transcription Factors; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tacrolimus

Topics: Cardiomegaly; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcineurin; Cardiomegaly; Echocardiography; Fibrosis; Gene Expression Regulation; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Stress, Mechanical; Tacrolimus; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cardiotoxicity has been described in a group of pediatric patients receiving FK506 as a part of immunosuppression for orthotopic liver transplantation (OLT). Information regarding the cardiac pathology related to this agent is limited.. Among the first 975 liver transplants at our institution (1985-1995), autopsy hearts were available for 19 patients (14 adults and 5 children) who received FK506 for a minimum of 1 week prior to death. Patients with excessive alcohol use, significant coronary artery disease, valvular disease, diabetes mellitus, or pretransplant hypertension were excluded from analysis. We compared heart weight (HW), heart weight-to-body weight ratio (HW/BW), ventricular septal (VS) thickness with left ventricular (LV) thickness ratio (VS/LV), and cardiac histologic findings of 12 OLT patients (7 adults, 5 children) who received FK506 with a group of 75 OLT patients (48 adults, 27 children) who received Cyclosporine (CsA) and 20 (10 adults, 10 children) age-comparable control patients without OLT.. All FK506 and CsA children and adults had cardiomegaly by HW, HW/BW (P(FK506 peds) <0.024, P(CsA peds)<0.028, P(FK506 adults) <0.017, P(CsA adults)<0.006) and increased VS/LV ratio 1.25(FK506) (P <0.006) and 1.23(CsA) (P <0.006)(pediatric) and 1.09(FK506) (P <0.0122) and 1.21(CsA) (P <0.0009)(adults), compared with control.. Cardiomegaly by HW, HW/BW, and histology was uniformly present in both FK506 and CsA adult and pediatric OLT patients at autopsy. A relatively greater VS hypertrophy than LV was present in both transplant groups. We found no gross or histologic cardiac finding that separated these FK506 from CsA OLT patients at autopsy.

Topics: Adult; Autopsy; Body Weight; Cardiomegaly; Child; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Organ Size; Tacrolimus

Topics: Adrenal Cortex Hormones; Autopsy; Cardiomegaly; Cyclosporine; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

It remains unclear how mineralocorticoids induce cardiac hypertrophy and fibrosis. Recently, activation of the calcium-dependent phosphatase, calcineurin, has been shown to induce cardiac hypertrophy. In the present study, we examine the role of calcineurin in mineralocorticoid-induced cardiac hypertrophy and fibrosis.. Uninephrectomized Wistar-Kyoto rats were placed on a 1.0% NaCl diet and treated with aldosterone (0.75 microg x h(-1)) for 6 weeks with or without the calcineurin inhibitors, FK506 (0.5 mg x kg(-1) x d(-1)) or cyclosporine A (10 mg x kg(-1) x d(-1)). The effect of the angiotensin II type 1 receptor antagonist, losartan (10 mg x kg(-1) x d(-1))on aldosterone-induced cardiac hypertrophy was also studied. Treatment with aldosterone increased the heart weight/body weight ratio, cardiomyocyte size, and collagen amount. The expression of mRNA of both type-III collagen and atrial natriuretic peptide in the heart were increased by aldosterone administration. Both calcineurin activity and its mRNA expression were also increased in aldosterone-induced hypertrophic heart. Treatment with losartan, FK506, or cyclosporine partially prevented aldosterone-induced cardiac hypertrophy and fibrosis.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy and fibrosis induced by mineralocorticoid excess. Inhibition of calcineurin may therefore prevent cardiac hypertrophy and fibrosis in mineralocorticoid hypertension.

Topics: Aldosterone; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Atrial Natriuretic Factor; Body Weight; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Collagen Type III; Cyclosporine; Enzyme Inhibitors; Fibrosis; Heart; Immunosuppressive Agents; Losartan; Male; Mineralocorticoids; Myocardium; Nephrectomy; Organ Size; Rats; Rats, Inbred WKY; RNA, Messenger; Sodium Chloride, Dietary; Tacrolimus

It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.. In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg every second day) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg every second day but not with 0.01 mg/kg every second day of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Hypertension; Male; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Tacrolimus

Cardiotrophin-1 (CT-1) is an interleukin-6 family cytokine with known protective and hypertrophic effects in the heart. Previous studies have shown that CT-1 treatment increases heat shock protein 70 (hsp70) and heat shock protein 90 (hsp90) levels in cardiac cells. Due to the known protective effects of hsp90 and hsp70, induction of these proteins may be involved in the protective effects of CT-1. We show here that heat shock protein 56 (hsp56), also known as FK506 binding protein 59 (FKBP59), is induced by CT-1 treatment at both the mRNA and protein levels. It has been demonstrated previously that, unlike hsp70 and hsp90, hsp56 overexpression does not protect cardiac myocytes against stressful stimuli. The other known effect of CT-1 is hypertrophy, an increase in cell size without cell division, which occurs in many cardiac pathologies. We investigated the role of hsp56 in the hypertrophic response of primary neonatal rat cardiac myocytes, using overexpression with transiently transfected plasmid vectors and Herpes viral vectors. Overexpression of hsp56 caused a significant increase in cardiac cell size and protein:DNA ratio. Hsp27, hsp70 and hsp90 overexpression had no effect on cell size. An antisense construct to hsp56 reduced hsp56 levels when transiently transfected and blocked the hypertrophic effect of CT-1. This is the first time that a hypertrophic effect has been demonstrated for a heat shock protein and demonstrates that CT-1-induced hypertrophy involves a specific hsp, which is not involved in its protective effect.

Topics: Animals; Animals, Newborn; Cardiomegaly; Cell Size; Cells, Cultured; Cytokines; DNA; Gene Expression; Genetic Vectors; Heat-Shock Proteins; Herpesvirus 1, Human; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Mice; Myocardium; Oligodeoxyribonucleotides, Antisense; Proteins; Rats; Rats, Sprague-Dawley; Tacrolimus; Tacrolimus Binding Proteins; Tumor Cells, Cultured

Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models.. To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency.. Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment.. The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Topics: Animals; Blood Pressure; Cachexia; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hypertension; Infections; Metabolism, Inborn Errors; Mice; Mice, Inbred C3H; Myocardium; Reference Values; Renal Insufficiency; Tacrolimus

Tacrolimus has been used as an immunosuppressive agent in the transplantation of all solid organs. Tacrolimus-induced hypertrophic cardiomyopathy has been reported to be an unusual but serious complication. To elucidate the effects of tacrolimus on myocardial hypertrophy, we studied the relationship between the blood levels of tacrolimus and cardiac wall thickening. Our findings demonstrated that tacrolimus-induced myocardial hypertrophy correlated with tacrolimus blood levels, and that myocardial hypertrophy induced by tacrolimus was reversible. However, no patients developed clinically significant symptoms related to myocardial hypertrophy.

Topics: Adolescent; Adult; Cardiomegaly; Child; Child, Preschool; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Tacrolimus

It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet.. In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment.. These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Topics: Animals; Blood Pressure; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Endomyocardial Fibrosis; Gene Expression Regulation; Heart; Hypertension; Injections, Intramuscular; Male; Myocardium; Rats; Rats, Inbred Dahl; Remission Induction; Sodium Chloride, Dietary; Tacrolimus

Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy.. Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment.. The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.

Topics: Animals; Aorta, Abdominal; Atrial Natriuretic Factor; Blood Volume; Body Weight; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Constriction, Pathologic; Disease Models, Animal; Echocardiography; Fibrosis; Gene Expression; Genes, Immediate-Early; Heart Rate; Immunosuppressive Agents; Male; Myocardium; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Signal Transduction; Tacrolimus

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiomegaly; Cells, Cultured; Cyclosporine; DNA-Binding Proteins; Enzyme Inhibitors; GATA4 Transcription Factor; Heart Failure; Humans; Mice; Myocardium; NFATC Transcription Factors; Nuclear Proteins; Signal Transduction; Tacrolimus; Transcription Factors

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiac Myosins; Cardiomegaly; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Carrier Proteins; Cyclosporine; Female; Mice; Mice, Transgenic; Microfilament Proteins; Models, Cardiovascular; Myocardium; Myosin Light Chains; Rats; Signal Transduction; Tacrolimus; Tropomodulin; Tropomyosin

Topics: Animals; Aorta; Calcineurin Inhibitors; Cardiomegaly; Cyclosporine; Immunosuppressive Agents; Ligation; Male; Rats; Rats, Sprague-Dawley; Tacrolimus