|
| ||
|
|
||
Calcineurin Inhibition (calcineurin + inhibition)
Selected AbstractsCalcineurin Inhibition Ameliorates Structural, Contractile, and Electrophysiologic Consequences of Postinfarction RemodelingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 9 2001LILI DENG M.S. Calcineurin Inhibition and Postinfarction Remodeling.Introduction: After myocardial infarction (MI), the heart undergoes an adaptive remodeling process characterized by hypertrophy of the noninfarcted myocardium. Calcineurin, a Ca2+, calmodulin-regulated phosphatase, has been shown to participate in hypertrophic signal transduction. Methods and Results: We investigated the effects of calcineurin inhibition by cyclosporin A on key structural, contractile, and electrophysiologic alterations of post-MI remodeling. Male Sprague-Dawley rats were divided into four groups: (1) sham-operated; (2) sham + cyclosporin A; (3) post-MI (left anterior descending coronary artery ligation); and (4) MI + cyclosporin A. Cyclosporin A (25 mg/kg/day) was initiated 2 days before surgery and continued for 30 days. Hypertrophy was evaluated by echocardiography and by changes in membrane capacitance of isolated myocytes from noninfarcted left ventricle (LV). The effects of cyclosporin A on hemodynamics and cardiac dimensions were investigated, and changes in diastolic function were correlated with changes in protein phosphatase 1 activity and the basal level of phosphorylated phospholamban. The effects of cyclosporin A on Kv4.2/Kv4.3 genes expression and transient outward K + current (Ito) density also were evaluated. One of 12 rats in the post-MI group and 2 of 12 rats in the post-MI + cyclosporin A group died within 48 hours after MI. There were no late deaths in either MI group. There was no evidence of heart failure (lung congestion and/or pleural effusion) in the two groups 4 weeks post-MI. Calcineurin phosphatase activity increased 1.9-fold in post-MI remodeled LV myocardium, and cyclosporin A administration resulted in an 86% decrease in activity. There were statistically significant decreases of LV end-diastolic pressure, LV end-diastolic diameter, and LV relative wall thickness in the post-MI + cyclosporin A group compared with the post-MI group. On the other hand, there was no significant difference in LV end-systolic diameter or peak rate of LV pressure increase between the two post-MI groups. Protein phosphatase 1 activity was elevated by 36% in the post-MI group compared with sham, and this correlated with a 79% decrease in basal level of p16, phospholamban. In the post-MI + cyclosporin A group, the increase in protein phosphatase 1 activity was much less (18% vs 36%; P < 0.05), and the decrease in basal level of p16-phospholamban was markedly ameliorated (20% vs 79%; P < 0.01). The decreases in mRNA levels of Kv4.2 and Kv4.3 and Ito density in the LV of the post-MI + cyclosporin A group were significantly less compared with the post-MI group. Conclusion: Our results show that calcineurin inhibition by cyclosporin A partially ameliorated post-MI remodeled hypertrophy, diastolic dysfunction, decrease in basal level of phosphorylated phospholamban, down-regulation of key K + genes expression, and decrease of K + current, with no adverse effects on systolic function or mortality in the first 4 weeks after MI. [source] Effects of Cyclosporine on Osteoclast Activity: Inhibition of Calcineurin Activity With Minimal Effects on Bone Resorption and Acid Transport Activity,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2003John P Williams Abstract Cyclosporine results in rapid and profound bone loss in transplant patients, an effect ascribed to osteoclasts. Cyclosporine, complexed with the appropriate immunophilin, inhibits calcineurin (the calcium/calmodulin dependent serine/threonine phosphatase) activity. We tested the hypothesis that cyclosporine inhibits calcineurin activity in osteoclasts, resulting in stimulation of osteoclast activity. We compared the effects of cyclosporine A and the calmodulin antagonist, tamoxifen, on bone resorption by avian osteoclasts. Tamoxifen inhibits bone resorption ,60%, whereas cyclosporine A only inhibited bone resorption 12%. One-hour treatment with 100 nM cyclosporine inhibited osteoclast calcineurin activity 70% in whole cell lysates, whereas 10 ,M tamoxifen only inhibited calcineurin activity 25%. We compared the effects of cyclosporine A and tamoxifen on acid transport activity in isolated membrane vesicles and in isolated membrane vesicles obtained from osteoclasts treated with cyclosporine A or tamoxifen under conditions that inhibit calcineurin activity. Direct addition of cyclosporine A in the acid transport assay, or pretreatment of cells with cyclosporine A followed by membrane isolation, had no effect on acid transport activity in membrane vesicles. In contrast, direct addition of tamoxifen to membranes inhibits acid transport activity, an effect that can be prevented by addition of exogenous calmodulin. Furthermore, acid transport activity was also inhibited in membrane vesicles isolated from cells treated with tamoxifen. In conclusion, cyclosporine A inhibits osteoclast calcineurin activity; however, calcineurin inhibition does not correspond to a significant effect on acid transport activity in isolated membrane vesicles or bone resorption by osteoclasts. [source] Calcineurin Inhibition Ameliorates Structural, Contractile, and Electrophysiologic Consequences of Postinfarction RemodelingJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 9 2001LILI DENG M.S. Calcineurin Inhibition and Postinfarction Remodeling.Introduction: After myocardial infarction (MI), the heart undergoes an adaptive remodeling process characterized by hypertrophy of the noninfarcted myocardium. Calcineurin, a Ca2+, calmodulin-regulated phosphatase, has been shown to participate in hypertrophic signal transduction. Methods and Results: We investigated the effects of calcineurin inhibition by cyclosporin A on key structural, contractile, and electrophysiologic alterations of post-MI remodeling. Male Sprague-Dawley rats were divided into four groups: (1) sham-operated; (2) sham + cyclosporin A; (3) post-MI (left anterior descending coronary artery ligation); and (4) MI + cyclosporin A. Cyclosporin A (25 mg/kg/day) was initiated 2 days before surgery and continued for 30 days. Hypertrophy was evaluated by echocardiography and by changes in membrane capacitance of isolated myocytes from noninfarcted left ventricle (LV). The effects of cyclosporin A on hemodynamics and cardiac dimensions were investigated, and changes in diastolic function were correlated with changes in protein phosphatase 1 activity and the basal level of phosphorylated phospholamban. The effects of cyclosporin A on Kv4.2/Kv4.3 genes expression and transient outward K + current (Ito) density also were evaluated. One of 12 rats in the post-MI group and 2 of 12 rats in the post-MI + cyclosporin A group died within 48 hours after MI. There were no late deaths in either MI group. There was no evidence of heart failure (lung congestion and/or pleural effusion) in the two groups 4 weeks post-MI. Calcineurin phosphatase activity increased 1.9-fold in post-MI remodeled LV myocardium, and cyclosporin A administration resulted in an 86% decrease in activity. There were statistically significant decreases of LV end-diastolic pressure, LV end-diastolic diameter, and LV relative wall thickness in the post-MI + cyclosporin A group compared with the post-MI group. On the other hand, there was no significant difference in LV end-systolic diameter or peak rate of LV pressure increase between the two post-MI groups. Protein phosphatase 1 activity was elevated by 36% in the post-MI group compared with sham, and this correlated with a 79% decrease in basal level of p16, phospholamban. In the post-MI + cyclosporin A group, the increase in protein phosphatase 1 activity was much less (18% vs 36%; P < 0.05), and the decrease in basal level of p16-phospholamban was markedly ameliorated (20% vs 79%; P < 0.01). The decreases in mRNA levels of Kv4.2 and Kv4.3 and Ito density in the LV of the post-MI + cyclosporin A group were significantly less compared with the post-MI group. Conclusion: Our results show that calcineurin inhibition by cyclosporin A partially ameliorated post-MI remodeled hypertrophy, diastolic dysfunction, decrease in basal level of phosphorylated phospholamban, down-regulation of key K + genes expression, and decrease of K + current, with no adverse effects on systolic function or mortality in the first 4 weeks after MI. [source] Review article: hepatitis C virus and calcineurin inhibition after renal transplantationALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2005F. FABRIZI Summary The impact of hepatitis C virus on patient and graft survival after renal transplantation remains controversial. However, recent studies have given emphasis on the detrimental role of hepatitis C on long-term patient and graft survival after renal transplantation. Various mechanisms can promote the lower survival in hepatitis C virus-positive recipients, i.e. post-transplant diabetes mellitus, liver disease and infections. Novel evidence has been accumulated showing the inhibitory activity of ciclosporin on the hepatitis C virus replication rate in human hepatocytes; ciclosporin has been shown in vitro to suppress hepatitis C virus replication as effectively as interferon alpha. This effect has not been seen with tacrolimus and is separate from its immunosuppressive activity. Data from patients with normal kidney function or after bone marrow transplantation show that ciclosporin inhibits hepatitis C virus replication. It appears that the progression of liver fibrosis is slower in hepatitis C virus-positive liver transplant recipients treated with ciclosporin than tacrolimus. In contrast, the clinical outcome of hepatitis C in hepatitis C virus-positive patients after liver transplantation treated with ciclosporin vs. tacrolimus has given mixed results. No information after renal transplantation is available. Various parameters can promote the worsening of hepatitis C after renal transplantation but choice of calcineurin inhibition is one of the few risk factors that can potentially be modified by the physician. Prospective, comparative trials of ciclosporin and tacrolimus with large size and adequate follow-up after renal transplantation are in progress. [source] Obesity, hyperlipidemia, and metabolic syndromeLIVER TRANSPLANTATION, Issue S2 2009Michael Charlton Key Points 1. Obesity is increasingly common among liver transplantation (LT) recipients and donors. Outcomes following LT for selected patients with class I-III obesity are similar to those for nonobese recipients. In patients who are otherwise satisfactory candidates for LT, a high body mass index, as long as it does not present a technical barrier, should not be considered to be an absolute contraindication to LT. 2. The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure (especially secondary to hepatitis C virus recurrence), malignancy, cardiovascular disease, infections, and renal failure. Metabolic syndrome is an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes, posttransplant hypertension, and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome, are all associated with an increased risk of post-LT mortality. Features of metabolic syndrome should be screened for and treated in LT recipients. 3. Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension. 4. It is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber). 5. Nonalcoholic steatohepatitis, an increasingly common etiology of cirrhosis and liver failure, recurs commonly after LT and may also arise de novo. Treatment should be directed at managing obesity and complications of metabolic syndrome. Optimal immunosuppression in patients with nonalcoholic steatohepatitis is still evolving but should include steroid minimization. Liver Transpl 15:S83,S89, 2009. © 2009 AASLD. [source] FK506 is neuroprotective in a model of antiretroviral toxic neuropathyANNALS OF NEUROLOGY, Issue 1 2003MRCP, Sanjay C. Keswani MBBS Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus,infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy. Ann Neurol 2003;53:000,000 [source] Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004S M Gardiner The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. CsA (5.9 mg kg,1 bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. Pretreatment with the angiotensin (AT1) receptor antagonist, losartan, and the endothelin (ETA and ETB) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the , -adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. Tacrolimus (450 ,g kg,1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. Sirolimus (450 ,g kg,1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects. British Journal of Pharmacology (2004) 141, 634,643. doi:10.1038/sj.bjp.0705659 [source] Effects of the combination of rapamycin with tacrolimus or cyclosporin on experimental intimal hyperplasiaBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 11 2002Dr J. R. Waller Background: Allograft vasculopathy remains the leading cause of late allograft failure following transplantation and can be inhibited by the antiproliferative drug rapamycin. This study assessed the efficacy of combining rapamycin therapy with calcineurin inhibition. Methods: Male Sprague,Dawley rats received rapamycin 0·05 mg/kg daily and either tacrolimus 0·1 mg/kg or cyclosporin 5 mg/kg daily, and findings were compared with those in an untreated control group. Animals underwent left common carotid artery balloon angioplasty; the artery was explanted after 2 weeks. Morphometric analysis was performed on transverse sections and the intima: media ratio was calculated. Profibrotic gene expression was measured with competitive reverse transcriptase,polymerase chain reaction at 14 and 28 days. Proliferation was determined with proliferating cell nuclear antigen at 14 and 28 days. Extracellular matrix deposition was quantified with Sirius red. Results: The combination of rapamycin and tacrolimus was associated with the greatest reduction in intimal thickening. Furthermore, treatment with rapamycin and tacrolimus significantly attenuated extracellular matrix deposition compared with rapamycin and cyclosporin (P < 0·02). Conclusion: The effects of rapamycin in combination with tacrolimus were better than those observed with rapamycin and cyclosporin. © 2002 British Journal of Surgery Society Ltd [source] Immunosuppression without calcineurin inhibition: optimization of renal function in expanded criteria donor renal transplantationCLINICAL TRANSPLANTATION, Issue 1 2009Patrick P.W. Luke Abstract:, Introduction:, To assess the efficacy of calcineurin inhibitor (CNI)-free immunosuppression vs. calcineurin-based immunosuppression in patients receiving expanded criteria donor (ECD) kidneys. Patient and methods:, Thirteen recipients of ECD kidneys were enrolled in this pilot study and treated with induction therapy and maintained on sirolimus, mycophenolate mofetil (MMF) and prednisone. A contemporaneous control group was randomly selected comprised of 13 recipients of ECD kidneys who had been maintained on CNI plus MMF and prednisone. Results:, For the study group vs. the control group, two-yr graft survival was 92.3% vs. 84.6% (p = NS), two-yr patient survival was 100% vs. 92.3% (p = NS) and the acute rejection rates were 23% vs. 31% (p = NS), respectively. Renal function was significantly better in the study group compared with control up to the six-month mark, after which, it remained numerically but not statistically significant. Complications were more common in the study group, but serious adverse events requiring discontinuation were rare. Conclusion:, This pilot study demonstrates that CNI-free regimens can be safely implemented in patients receiving ECD kidneys with excellent two-yr patient and graft survival and good renal allograft function. Longer follow-up in larger randomized controlled trials are necessary to establish these findings. [source] | ||||||||||