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      Atorvastatin Treatment Prevents Alterations in Coronary Smooth Muscle Nuclear Ca 2+ Signaling in Diabetic Dyslipidemia

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          Abstract

          Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alters bulk myoplasmic Ca<sup>2+</sup> regulation and inhibits phenotypic modulation and proliferation of vascular smooth muscle in culture. Nuclear Ca<sup>2+</sup> (Ca<sub>n</sub>) signaling is tightly coupled to transcriptional events and cell growth. Therefore, we hypothesized that in vivo treatment with atorvastatin would attenuate alterations in mitogen-induced Ca<sub>n</sub> signaling associated with coronary atherosclerosis. Three groups of male Yucatan pigs were treated for 20 weeks: controls, alloxan-induced diabetics fed an atherogenic diet and diabetics fed an atherogenic diet plus atorvastatin (80 mg/day). Right coronary artery single-cell cytosolic Ca<sup>2+</sup> (Ca<sub>c</sub>) and Ca<sub>n</sub> responses to the mitogen endothelin-1 (5 × 10<sup>–8</sup> M) were measured by laser confocal microscopy using the calcium indicator Fluo-4. We observed a 39% increase in Ca<sub>c</sub> and a 52% increase in Ca<sub>n</sub> responses to endothelin-1 in cells from diabetic dyslipidemic arteries compared to control. These alterations were prevented in animals treated with atorvastatin. We show that during proliferation, the nucleus of a smooth muscle cell becomes rounded and loses the characteristic multilobular shape, clefts and invaginations. Consistent with this, a redistribution of Ca<sup>2+</sup> stores from a transnuclear morphology in controls to a more perinuclear morphology occurred in cells from diabetic dyslipidemic arteries and was prevented by atorvastatin. In addition, the peak Ca<sub>n</sub> responses to endothelin-1 were inversely correlated (r = 0.712) with the extent of the transnuclear distribution of Ca<sup>2+</sup> stores and directly correlated (r = 0.874) with the extent of atherosclerosis, as assessed in vivo by intravascular ultrasound. These findings indicate that chronic treatment with atorvastatin directly decreases mitogen-induced Ca<sub>n</sub> mobilization, which we suggest is related to the spatial localization of Ca<sub>n</sub> stores.

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          Most cited references 9

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          Effect of Statins on Risk of Coronary Disease

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            CBP: a signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV.

            Recruitment of the coactivator, CREB binding protein (CBP), by signal-regulated transcription factors, such as CREB [adenosine 3', 5'-monophosphate (cAMP) response element binding protein], is critical for stimulation of gene expression. The mouse pituitary cell line AtT20 was used to show that the CBP recruitment step (CREB phosphorylation on serine-133) can be uncoupled from CREB/CBP-activated transcription. CBP was found to contain a signal-regulated transcriptional activation domain that is controlled by nuclear calcium and calcium/calmodulin-dependent (CaM) protein kinase IV and by cAMP. Cytoplasmic calcium signals that stimulate the Ras mitogen-activated protein kinase signaling cascade or expression of the activated form of Ras provided the CBP recruitment signal but did not increase CBP activity and failed to activate CREB- and CBP-mediated transcription. These results identify CBP as a signal-regulated transcriptional coactivator and define a regulatory role for nuclear calcium and cAMP in CBP-dependent gene expression.
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              Diabetes mellitus: a disease of abnormal cellular calcium metabolism?

              Although the pathogenesis of the diabetes mellitus syndrome remains poorly understood, both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus predispose the individual to a similar spectrum of complications, including hypertension, macrovascular and microvascular disease, cataracts cardiomyopathy, neuropathy, and premature aging, suggesting that these complications develop along a pathway common to both diabetic conditions. Yet not all diabetic persons are affected by all of these complications or to the same degree. What causes this marked variability in the clinical manifestations of the diabetes syndrome remains an enigma. Accumulating data from animal models of diabetes and from studying patients with diabetes reveal that intracellular calcium levels are increased in most tissues. The activities of the membrane, adenosine triphosphatase (ATPase) associated cation pumps, which determine intracellular calcium level (i.e., calcium-ATPase and [sodium + potassium]-ATPase), are also altered. The nature of the alteration is often tissue specific and may depend on the level of blood glucose or insulin, or both. In this review we discuss the potential contribution of these changes in intracellular calcium regulation, whether acquired or genetically determined, to the pathogenesis of the diabetes syndrome, to the abnormalities in insulin secretion and action (mainly in non-insulin-dependent diabetes), and to the complications of both diabetes syndromes. Altered intracellular calcium metabolism may represent a common, underlying abnormality linking the metabolic, cardiovascular, ocular, and neural manifestations of the diabetic disease process.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2002
                June 2002
                22 August 2008
                : 39
                : 3
                : 208-220
                Affiliations
                Departments of aPhysiology and bInternal Medicine, School of Medicine, cDalton Cardiovascular Research Center, dDiabetes and Cardiovascular Biology Program, University of Missouri, Columbia, Mo., USA
                Article
                63686 J Vasc Res 2002;39:208–220
                10.1159/000063686
                12097819
                © 2002 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 6, Tables: 2, References: 51, Pages: 13
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