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Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

ABSTRACT: Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown.We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function.CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.

SUBMITTER: Toko H

PROVIDER: S-EPMC3226824 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

Toko Haruhiro H Takahashi Hidehisa H Kayama Yosuke Y Oka Toru T Minamino Tohru T Okada Sho S Morimoto Sachio S Zhan Dong-Yun DY Terasaki Fumio F Anderson Mark E ME Inoue Masashi M Yao Atsushi A Nagai Ryozo R Kitaura Yasushi Y Sasaguri Toshiyuki T Komuro Issei I

Circulation 20100816 9

<h4>Background</h4>Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown.<h4>Methods and results</h4>We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been report ...[more]

PMID: 20713897

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Project description:AimsThe aims of this paper were to investigate the analytical performance of the nine prognostic scales commonly used in heart failure (HF), in patients with dilated cardiomyopathy (DCM), and to develop a unique prognostic model tailored to DCM patients.Methods and resultsThe hospital and outpatient records of 406 DCM patients were retrospectively analysed. The information on patient status was gathered after 48.2 ± 32.0 months. Tests were carried out to ascertain the prognostic accuracy in DCM using some of the most frequently applied HF prognostic scales (Barcelona Bio-Heart Failure, Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity, Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, Meta-Analysis Global Group in Chronic Heart Failure, MUerte Subita en Insuficiencia Cardiaca, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, Seattle Heart Failure Model) and one dedicated to DCM, that of Miura et al. At follow-up, 70 DCM patients (17.2%) died. Most analysed scores substantially overestimated the mortality risk, especially in survivors. The prognostic accuracy of the scales were suboptimal, varying between 60% and 80%, with the best performance from Barcelona Bio-Heart Failure and Seattle Heart Failure Model for 1-5 year mortality [areas under the receiver operating curve 0.792-0.890 (95% confidence interval 0.725-0.918) and 0.764-0.808 (95% confidence interval 0.682-0.934), respectively].Based on our accumulated data, a self-developed DCM prognostic model was constructed. The model consists of age, gender, body mass index, symptoms duration, New York Heart Association class, diabetes mellitus, prior stroke, abnormal liver function, dyslipidaemia, left bundle branch block, left ventricle end-diastolic diameter, ejection fraction, N terminal pro brain natriuretic peptide, haemoglobin, estimated glomerular filtration rate, and pharmacological and resynchronisation therapy. This newly created prognostic model outperformed the analysed HF scales.ConclusionsAn analysis of various HF prognostic models found them to be suboptimal for DCM patients. A self-developed DCM prognostic model showed improved performance over the nine other models studied. However, further validation of the prognostic model in different DCM populations is required.

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Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

Publications

Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

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