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      Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

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          Abstract

          Troponin, a contractile protein of the thin filament of striated muscle, consists of three subunits: troponin C (TnC), troponin T (TnT), and troponin I (TnI). Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. The physiological effect of cTnI, as an inhibitory subunit of troponin complex, is to prevent the interaction between myosin heavy chain heads and actins, i.e. the cross-bridge formation, and to ensure a proper relaxation of cardiac myofilaments. In pathological conditions, the deficiency of cTnI or mutations in cTnI especially in the C-terminus of cTnI is associated with diastolic dysfunction caused by myofibril hypersensitivity to Ca 2+. Our laboratory has generated cTnI knockout mouse model to investigate the cellular and molecular function of cTnI and created cTnI mutant disease mouse models to explore the pathophysiology caused by cTnI mutations in the heart. Here, we present our recent studies on physiological function of cTnI in the heart and the pathological consequences caused by the cTnI mutations in the diseased heart using the transgenic mouse models. The mechanisms underlying diastolic dysfunction and heart failure caused by cTnI mutations are explored in cell-based assays and in transgenic animal models. These studies provide us with useful information in searching for therapeutic strategies and target-oriented medication for the treatment of diastolic dysfunction and heart failure.

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          Most cited references11

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          Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations.

          The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC). Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease. Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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            Correcting diastolic dysfunction by Ca2+ desensitizing troponin in a transgenic mouse model of restrictive cardiomyopathy.

            Several cardiac troponin I (cTnI) mutations are associated with restrictive cardiomyopathy (RCM) in humans. We have created transgenic mice (cTnI(193His) mice) that express the corresponding human RCM R192H mutation. Phenotype of this RCM animal model includes restrictive ventricles, biatrial enlargement and sudden cardiac death, which are similar to those observed in RCM patients carrying the same cTnI mutation. In the present study, we modified the overall cTnI in cardiac muscle by crossing cTnI(193His) mice with transgenic mice expressing an N-terminal truncated cTnI (cTnI-ND) that enhances relaxation. Protein analyses determined that wild type cTnI was replaced by cTnI-ND in the heart of double transgenic mice (Double TG), which express only cTnI-ND and cTnI R193H in cardiac myocytes. The presence of cTnI-ND effectively rescued the lethal phenotype of RCM mice by reducing the mortality rate. Cardiac function was significantly improved in Double TG mice when measured by echocardiography. The hypersensitivity to Ca(2+) and the prolonged relaxation of RCM cTnI(193His) cardiac myocytes were completely reversed by the presence of cTnI-ND in RCM hearts. The results demonstrate that myofibril hypersensitivity to Ca(2+) is a key mechanism that causes impaired relaxation in RCM cTnI mutant hearts and Ca(2+) desensitization by cTnI-ND can correct diastolic dysfunction and rescue the RCM phenotypes, suggesting that Ca(2+) desensitization in myofibrils is a therapeutic option for treatment of diastolic dysfunction without interventions directed at the systemic beta-adrenergic-PKA pathways. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Cardiac troponin I gene knockout: a mouse model of myocardial troponin I deficiency.

              Troponin I is a subunit of the thin filament-associated troponin-tropomyosin complex involved in calcium regulation of skeletal and cardiac muscle contraction. We deleted the cardiac isoform of troponin I by using gene targeting in murine embryonic stem cells to determine the developmental and physiological effects of the absence of this regulatory protein. Mice lacking cardiac troponin I were born healthy, with normal heart and body weight, because a fetal troponin I isoform (identical to slow skeletal troponin I) compensated for the absence of cardiac troponin I. Compensation was only temporary, however, as 15 days after birth slow skeletal troponin I expression began a steady decline, giving rise to a troponin I deficiency. Mice died of acute heart failure on day 18, demonstrating that some form of troponin I is required for normal cardiac function and survival. Ventricular myocytes isolated from these troponin I-depleted hearts displayed shortened sarcomeres and elevated resting tension measured under relaxing conditions and had a reduced myofilament Ca sensitivity under activating conditions. The results show that (1) developmental downregulation of slow skeletal troponin I occurs even in the absence of cardiac troponin I and (2) the resultant troponin I depletion alters specific mechanical properties of myocardium and can lead to a lethal form of acute heart failure.
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                Author and article information

                Journal
                GSTF J Adv Med Res
                GSTF J Adv Med Res
                Gstf Journal of Advances in Medical Research
                Global Science and Technology Forum (Singapore )
                2345-721X
                9 July 2015
                9 July 2015
                2014
                : 1
                : 2
                : 17
                Affiliations
                [1 ]pediatrics research institute in Children’s hospital, Chongqing Medical University, Chongqing, China
                [2 ]Children’s Hospital, Chongqing Medical University, Chongqing, China
                Article
                17
                10.7603/s40782-014-0017-6
                5302009
                28239629
                0f86cf7f-5e6a-446d-83e7-59f1ac9c041b
                © Global Science and Technology Forum 2014
                History
                : 23 January 2015
                : 23 February 2015
                Categories
                Original Paper
                Custom metadata
                © The Author(s) 2014

                myofilament,gene mutation,cardiomyopathy,heart failure,transgenic mice

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