Alterations in myofibrillar function and protein profiles after complete global ischemia in rat hearts.

Westfall, Margaret V.; Solaro, R. John

doi:10.1161/01.res.70.2.302

Cited by 77 publications

(50 citation statements)

References 34 publications

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“…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). TnI can dramatically decrease in postinfarction left ventricular (LV) remodeled myocardium remote from the infarct zone (24), and the content of TnI in LV myocardium may significantly decrease in older men with or without cardiac disease (37).…”

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confidence: 97%

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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confidence: 97%

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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“…Fetal rat hearts express a TnI isoform that is similar to the slow skeletal troponin I (ssTnI) isoform, which is replaced by a cardiac TnI (cTnI) isoform at around the time of birth (5,7,15,24,50,52). This isoform shift is linked to a marked decrease in Ca 2ϩ sensitivity of force development occurring in rats (and mice) during the postnatal period (16,46,53,59). Again, the identity of the trigger(s) responsible for a coordinated isoform switching of several sarcomere proteins, including titin and TnI, has remained obscure, although available data perhaps suggested a signaling cascade that is somehow initiated by birth.…”

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confidence: 99%

Developmental changes in passive stiffness and myofilament Ca²⁺sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

Kohl¹,

Linke²

2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Developmental changes in passive stiffness and myofilament Ca 2ϩ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth. Am J Physiol Heart Circ Physiol 291: H496 -H506, 2006. First published May 5, 2006; doi:10.1152/ajpheart.00114.2006.-The giant protein titin, a major contributor to myocardial mechanics, is expressed in two main cardiac isoforms: stiff N2B (3.0 MDa) and more compliant N2BA (Ͼ3.2 MDa). Fetal hearts of mice, rats, and pigs express a unique N2BA isoform (ϳ3.7 MDa) but no N2B. Around birth the fetal N2BA titin is replaced by smaller-size N2BA isoforms and N2B, which predominates in adult hearts, stiffening their sarcomeres. Here we show that perinatal titin-isoform switching and corresponding passive stiffness (STp) changes do not occur in the hearts of guinea pig and sheep. In these species the shift toward "adult" proportions of N2B isoform is almost completed by midgestation. The relative contributions of titin and collagen to STp were estimated in force measurements on skinned cardiac muscle strips by selective titin proteolysis, leaving the collagen matrix unaffected. Titin-based STp contributed between 42% and 58% to total STp in late-fetal and adult sheep/guinea pigs and adult rats. However, only ϳ20% of total ST p was titin based in late-fetal rat. Titin-borne passive tension and the proportion of titin-based ST p generally scaled with the N2B isoform percentage. The titin isoform transitions were correlated to a switch in troponin-I (TnI) isoform expression. In rats, fetal slow skeletal TnI (ssTnI) was replaced by adult carciac TnI (cTnI) shortly after birth, thereby reducing the Ca 2ϩ sensitivity of force development. In contrast, guinea pig and sheep coexpressed ssTnI and cTnI in fetal hearts, and skinned fibers from guinea pig showed almost no perinatal shift in Ca 2ϩ sensitivity. We conclude that TnI-isoform and titin-isoform switching and corresponding functional changes during heart development are not initiated by birth but are genetically programmed, species-specific regulated events. heart development; connectin; elasticity; myocardium BIRTH IS A DRAMATIC EVENT in mammalian heart development. With the newborn's first breaths of air, the fetal circulation changes, and cardiac pump function is intensified to keep up with the increased power requirements of the newborn that suddenly lacks placental nurturing and oxygen supply. Heart rate, end-diastolic pressure, stroke volume, and left ventricular (LV) dimensions all increase to meet the metabolic demands of newborn life (4, 26). During perinatal development of myocardium, many sarcomere proteins alter their isoform pattern rather rapidly. Among them are the contractile proteins myosin heavy chain (MyHC) (9, 22, 32, 53) and ␣-actin (10); regulatory proteins, including troponin-I (TnI), troponin-T (TnT), tropomyosin (36,46,(51)(52)(53), and myosin light chain-1 (60); and scaffolding proteins such as myomesin (1) and titin (27,41,43, 56). However, as these studies have usually been performed ...

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“…Among these effects is a depressed contractile function of the myocardium associated with a prominent decreased sensitivity of myofilaments to Ca 2ϩ (16,19). One proposed molecular mechanism for this effect has been proteolysis of sarcomeric proteins, especially cardiac troponin I (cTnI) (49). I/R-induced proteolytic cleavage of 18 amino acids at the COOH terminus of TnI has been demonstrated to depress maximal tension similar to that seen in stunning (34).…”

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Specific enhancement of sarcomeric response to Ca²⁺protects murine myocardium against ischemia-reperfusion dysfunction

Arteaga

Warren

Milutinović

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Alteration in myofilament response to Ca 2ϩ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca 2ϩ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice with a constitutive increase in myofilament Ca 2ϩ sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD-57033, which acts specifically to enhance myofilament response to Ca 2ϩ . We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end-diastolic pressure was significantly elevated in nontransgenic (NTG) control hearts. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels. Ca 2ϩ -and cross bridge-dependent activation, protein breakdown, and phosphorylation in detergent-extracted fiber bundles were also investigated. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca 2ϩ -activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca 2ϩ sensitivity are able to diminish the effect of I/R on cardiac function.

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Alterations in myofibrillar function and protein profiles after complete global ischemia in rat hearts.

Cited by 77 publications

References 34 publications

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

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

Developmental changes in passive stiffness and myofilament Ca²⁺sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

Specific enhancement of sarcomeric response to Ca²⁺protects murine myocardium against ischemia-reperfusion dysfunction

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Alterations in myofibrillar function and protein profiles after complete global ischemia in rat hearts.

Cited by 77 publications

References 34 publications

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

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

Developmental changes in passive stiffness and myofilament Ca2+sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

Specific enhancement of sarcomeric response to Ca2+protects murine myocardium against ischemia-reperfusion dysfunction

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Developmental changes in passive stiffness and myofilament Ca²⁺sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

Specific enhancement of sarcomeric response to Ca²⁺protects murine myocardium against ischemia-reperfusion dysfunction