Heart Failure, Myocardial Stunning, and Troponin: A Key Regulator of the Cardiac Myofilament

Murphy, Anne M.

doi:10.1111/j.1527-5299.2006.04320.x

Cited by 24 publications

(23 citation statements)

References 63 publications

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“…However, stunning persisted in late reperfusion in cells from both groups, despite recovery of Ca 2ϩ transient amplitudes. This suggests that reduced myofilament Ca 2ϩ sensitivity in reperfusion, which is believed to contribute importantly to the pathogenesis of stunning (15,40), occurs equally in individual cells from young adult and aged rat hearts.…”

Section: Discussionmentioning

confidence: 93%

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

O'Brien¹,

Ferguson²,

Howlett³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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This study examined the impact of age on contractile function, Ca(2+) homeostasis, and cell viability in isolated myocytes exposed to simulated ischemia and reperfusion. Ventricular myocytes were isolated from anesthetized young adult (3 mo) and aged (24 mo) male Fischer 344 rats. Cells were field-stimulated at 4 Hz (37 degrees C), exposed to simulated ischemia, and reperfused with Tyrode solution. Cell shortening and intracellular Ca(2+) were measured simultaneously with an edge detector and fura-2. Cell viability was assessed by Trypan blue exclusion. Ischemia (20-45 min) depressed amplitudes of contraction equally in isolated myocytes from young adult and aged animals. The degree of postischemic contractile depression (stunning) was comparable in both groups. Ca(2+) transient amplitudes were depressed in early reperfusion in young adult and aged cells and then recovered to preischemic levels in both groups. Cell viability also declined equally in reperfusion in both groups. In short, some cellular responses to simulated ischemia and reperfusion were similar in both groups. Even so, aged myocytes exhibited a much greater and more prolonged accumulation of diastolic Ca(2+) in ischemia and in early reperfusion compared with myocytes from younger animals. In addition, the degree of mechanical alternans in ischemia increased significantly with age. The observation that there is an age-related increase in accumulation of diastolic Ca(2+) in ischemia and early reperfusion may account for the increased sensitivity to ischemia and reperfusion injury in the aging heart. The occurrence of mechanical alternans in ischemia may contribute to contractile dysfunction in ischemia in the aging heart.

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Section: Discussionmentioning

confidence: 93%

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

O'Brien¹,

Ferguson²,

Howlett³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Although having no effect on the anchoring strength of TnT on tropomyosin, the altered binding affinity of NH 2 -terminal truncated cTnT for tropomyosin may affect the allosteric feature of the thin filament regulatory system, contributing to myocardial function during ischemia reperfusion. Intracellular acidosis occurs in myocardial ischemic injury with a correlation to the function of troponin (49). Therefore, we compared the response of cTnT-ND to lowered pH with that of intact cTnT.…”

Section: Similar Nh 2 -Terminal Truncation Of Cardiac and Fast Skeletmentioning

confidence: 98%

Selective Deletion of the NH₂-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by Myofibril-Associated μ-Calpain Cleavage

2006

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The structure of the NH2-terminal region of troponin T (TnT) is hypervariable among the muscle type-specific isoforms and is also regulated by alternative RNA splicing. This region does not contain binding sites for other thin filament proteins, but alteration of its structure affects the Ca2+ regulation of muscle contraction. Here we report a truncated cardiac TnT produced during myocardial ischemia reperfusion. Amino acid sequencing and protein fragment reconstruction determined that it is generated by a posttranslational modification selectively removing the NH2-terminal variable region and preserving the conserved core structure of TnT. Triton X-100 extraction of cardiac muscle fibers promoted production of the NH2-terminal truncated cardiac TnT (cTnT-ND), indicating a myofibril-associated proteolytic activity. Mu-calpain is a myofibril-associated protease and is known to degrade TnT. Supporting a role of mu-calpain in producing cTnT-ND in myocardial ischemia reperfusion, calpain inhibitors decreased the level of cTnT-ND in Triton-extracted myofibrils. Mu-calpain treatment of the cardiac myofibril and troponin complex specifically reproduced cTnT-ND. In contrast, mu-calpain treatment of isolated cardiac TnT resulted in nonspecific degradation, suggesting that this structural modification is relevant to physiological structures of the myofilament. Triton X-100 treatment of transgenic mouse cardiac myofibrils overexpressing fast skeletal muscle TnT produced similar NH2-terminal truncations of the endogenous and exogenous TnT, despite different amino acid sequences at the cleavage site. With the functional consequences of removing the NH2-terminal variable region of TnT, the mu-calpain-mediated proteolytic modification of TnT may act as an acute mechanism to adjust muscle contractility under stress conditions.

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“…The increased availability of intracellular Ca 2ϩ in preconditioned cells would provide more Ca 2ϩ to activate contraction (5). This could help to counteract the decrease in myofilament Ca 2ϩ sensitivity that contributes importantly to the pathogenesis of postischemic contractile depression and stunning in reperfusion (42).…”

Section: Discussionmentioning

confidence: 99%

Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts

O'Brien¹,

Howlett²

2008

American Journal of Physiology-Heart and Circulatory Physiology

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O'Brien JD, Howlett SE. Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts. Am J Physiol Heart Circ Physiol 295: H768 -H777, 2008; doi:10.1152/ajpheart.00432.2008.-The impact of ischemic preconditioning (IPC) on contraction, Ca 2ϩ homeostasis, and cell survival was compared in isolated ventricular myocytes from young adult (ϳ3 mo) and aged (ϳ24 mo) male Fischer-344 rats. Myocytes were field stimulated at 4 Hz (37°C). Contraction (edge detector) and intracellular Ca 2ϩ (fura-2) were measured simultaneously. Viability was assessed with trypan blue. All cells were exposed to 30 min of simulated ischemia followed by reperfusion. Some cells were preconditioned by exposure to 5 min of simulated ischemia before prolonged ischemia. Pretreatment with IPC abolished postischemic contractile depression, inhibited diastolic contracture, and increased Ca 2ϩ transient amplitudes in reperfusion in young adult and aged cells. IPC did not affect the modest rise in diastolic Ca 2ϩ in ischemia in young adult myocytes. However, IPC abolished the marked rise in diastolic Ca 2ϩ observed in ischemia and early reperfusion in aged myocytes. IPC also suppressed mechanical alternans in ischemia in aged cells, but younger myocytes showed little evidence of mechanical alternans whether or not cells were preconditioned. IPC markedly improved cell viability in reperfusion in young adult but not aged cells. These results suggest that IPC augments the recovery of contractile function in reperfusion by increasing Ca 2ϩ transient amplitudes in ventricular myocytes from young adult and aged rats. IPC reduced diastolic Ca 2ϩ accumulation in ischemia in aged myocytes, which may diminish the severity of mechanical alternans in aged cells. Nonetheless, the efficacy of IPC is compromised in aging, as IPC did not improve survival of aged myocytes exposed to ischemia and reperfusion. cardioprotection; reperfusion; mechanical alternans; senescence IT IS WELL ESTABLISHED that aged hearts are more sensitive to ischemia and reperfusion injury than younger adult hearts (14,22,27). Studies in humans have shown that morbidity and mortality rates after acute myocardial infarction are much higher in older adults than in younger patients (37,50,54). Also, the risk of death following procedures that cause reperfusion increases with age (9, 53). Similar results have been reported in animal models of aging. Studies of ischemia and reperfusion injury in Langendorff-perfused hearts have shown that infarct size is greater in hearts from aged animals than in younger hearts, while recovery of contractile function in reperfusion declines with age (3,16,19,31,39,48,55). Many of these detrimental effects of myocardial ischemia and reperfusion are thought to be linked to a rise in intracellular free Ca 2ϩ levels in cardiac myocytes (30,40). Indeed, individual ventricular myocytes isolated from aged rats accumulate more diastolic Ca 2ϩ in ischemia and early reperfusion than cells from younger hearts (43)....

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Heart Failure, Myocardial Stunning, and Troponin: A Key Regulator of the Cardiac Myofilament

Cited by 24 publications

References 63 publications

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

Selective Deletion of the NH₂-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by Myofibril-Associated μ-Calpain Cleavage

Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts

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Heart Failure, Myocardial Stunning, and Troponin: A Key Regulator of the Cardiac Myofilament

Cited by 24 publications

References 63 publications

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts

Selective Deletion of the NH2-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by Myofibril-Associated μ-Calpain Cleavage

Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts

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Selective Deletion of the NH₂-Terminal Variable Region of Cardiac Troponin T in Ischemia Reperfusion by Myofibril-Associated μ-Calpain Cleavage