A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice

Du, Ji-Zeng; Zhang, C.; Liu, J.; Sidky, C.; Huang, Xiongjian

doi:10.1016/j.abb.2006.08.018

Cited by 43 publications

(53 citation statements)

References 23 publications

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“…In 1 model, transgenic mice carrying the R193H mutation (analogous to the R192H mutation associated with restrictive cardiomyopathy in humans), developed atrial dilation with reduced LV chamber size and increased chamber stiffness in the absence of increased wall thickness. 200,201 In comparison with nontransgenic littermates, mice with the R193H cTnI mutation demonstrate a reduced resting cardiac output, reduced contractile reserve in response to dobutamine, and a higher mortality by 12 months of age. 200 Studies in the cTnI R145W mouse have shown that the same cTnI locus can be associated with either a hypertrophic or a restrictive cardiomyopathy phenotype (in both humans or mice) depending on which base pair is substituted at the locus.…”

Section: Restrictive Cardiomyopathy: Current Animal Modelsmentioning

confidence: 99%

Animal Models of Heart Failure

Houser¹,

Margulies²,

Murphy³

et al. 2012

Circulation Research

383

219

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Section: Restrictive Cardiomyopathy: Current Animal Modelsmentioning

confidence: 99%

Animal Models of Heart Failure

Houser¹,

Margulies²,

Murphy³

et al. 2012

Circulation Research

383

219

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“…The transgenic mice carrying RCM cTnI R193H mutation (cTnI 193His ) had 20-40% mortality rates and developed RCM phenotype similar to that observed in RCM patients [3]. However, cTnI 178Glu and cTnI 205His mice were lethal and died a couple of days after birth.…”

Section: B Create Transgenic Mice With Rcm Ctni Mutationsmentioning

confidence: 79%

“…Our laboratory is among the first in studying the molecular mechanisms and pathophysiology of diastolic dysfunction and diastolic heart failure in transgenic mouse models. We have generated cardiac troponin I (cTnI) gene knockout mouse model [2] and transgenic mice with cTnI C-terminal mutations [3,4]. Using these animal models, we have explored the physiological roles of troponin in cardiac muscle movement and cardiac function and revealed the mechanisms underlying cardiac dysfunction and heart disorders caused by the troponin mutations in myocardial cells.…”

Section: Introductionmentioning

confidence: 99%

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

Xu¹,

Tian²,

Huang³

2014

JAMR

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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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“…Its role in mediating cardiac dysfunction in humans and experimental animals is controversial and continues to be actively investigated. Linkage studies and animal experiments have confirmed that point mutations in cTnI are linked to hypertrophic cardiomyopathy (1,11,14,27) or restrictive cardiomyopathy (4,20). TnI degradation has been reported in myocardial cells after ischemia and cardiac stunning (7,15,21,39).…”

mentioning

confidence: 96%

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Liu

Zhang³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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XP. Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice. Am J Physiol Heart Circ Physiol 293: H1273-H1281, 2007. First published May 25, 2007; doi:10.1152/ajpheart.01379.2006.-Cardiac troponin I (TnI) knockout mice exhibit a phenotype of sudden death at 17-18 days after birth due to a progressive loss of TnI. The objective of this study was to gain insight into the physiological consequences of TnI depletion and the cause of death in these mice. Cardiac function was monitored serially between 12 and 17 days of age by using high-resolution ultrasonic imaging and Doppler echocardiography. Two-dimensional B-mode and anatomical M-mode imaging and Doppler echocardiography were performed using a high-frequency (ϳ20 -45 MHz) ultrasound imaging system on homozygous cardiac TnI mutant mice (cTnI Ϫ/Ϫ ) and wild-type littermates. On day 12, cTnI Ϫ/Ϫ mice were indistinguishable from wildtype mice in terms of heart rate, atrial and LV (LV) chamber dimensions, LV posterior wall thickness, and body weight. By days 16 through 17, wild-type mice showed up to a 40% increase in chamber dimensions due to normal growth, whereas cTnI Ϫ/Ϫ mice showed increases in atrial dimensions of up to 97% but decreases in ventricular dimensions of up to 70%. Mitral Doppler analysis revealed prolonged isovolumic relaxation time and pronounced inversion of the mitral E/A ratio (early ventricular filling wave-to-late atrial contraction filling wave) only in cTnI Ϫ/Ϫ mice indicative of impaired LV relaxation. cTnI Ϫ/Ϫ mouse hearts showed clear signs of failure on day 17, characterized by Ͼ50% declines in cardiac output, ejection fraction, and fractional shortening. B-mode echocardiography showed a profoundly narrowed tube-like LV and enlarged atria at this time. Our data are consistent with TnI deficiency causing impaired LV relaxation, which leads to diastolic heart failure in this model. damaged relaxation; echocardiography; Doppler analysis THE CONTRACTILE SARCOMERIC PROTEINS consist of a highly ordered arrangement of myosin thick filaments, actin thin filaments, and associated proteins, such as the troponin-tropomyosin complex. Contractile sarcomeric protein mutations, truncations, and deletions have been identified for various cardiac disorders in humans and experimental animals (8,16,18,23,25,28

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A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice

Cited by 43 publications

References 23 publications

Animal Models of Heart Failure

Animal Models of Heart Failure

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

Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

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