Protein kinase Cε induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism

@article{Montgomery2005ProteinKC,
  title={Protein kinase C$\epsilon$ induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism},
  author={David E. Montgomery and Veronica L. M. Rundell and Paul H. Goldspink and Dalia Urboniene and David L. Geenen and Pieter P. de Tombe and Peter Buttrick},
  journal={American Journal of Physiology-heart and Circulatory Physiology},
  year={2005},
  volume={289}
}
Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac overexpression of PKCe initially depresses myofilament activity and then l... 

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Augmented Protein Kinase C-α–Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure

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Impaired β‐adrenergic responsiveness accentuates dysfunctional excitation–contraction coupling in an ovine model of tachypacing‐induced heart failure

It is shown that in heart failure the response to β‐receptor stimulation is reduced and this appears to be due to a failure to signal correctly to downstream targets inside the cell, which provides a number of potential targets for therapies to improve the function of the heart in patients with heart failure.

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References

SHOWING 1-10 OF 35 REFERENCES

Protein Kinase C&egr; Overexpression Alters Myofilament Properties and Composition During the Progression of Heart Failure

Characterization of a transgenic mouse that overexpresses constitutively active protein kinase C&egr; in the heart and slowly develops a dilated cardiomyopathy with failure is reported to implicate the disruption of the myofibrillar proteins and their interactions in the propagation of dilated cardiac disease.

alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI.

Evidence is provided that specific PKC-mediated phosphorylation of Ser(43) and Ser(45) of cTnI plays an important role in regulating force development in the intact myocardium.

Protein kinase A does not alter economy of force maintenance in skinned rat cardiac trabeculae.

Recent mechanical, biochemical, and energetic experiments have suggested that catecholamines may increase the cycling rate of cross-bridges independent of changes inn intracellular calcium. An

Depressed cardiac tension cost in experimental diabetes is due to altered myosin heavy chain isoform expression.

The depression of tension cost in this rodent model of diabetes could be fully explained by the altered myosin isoform distribution, as demonstrated by a linear decrease in tension cost with decreased alpha-myosin content.

Troponin I serines 43/45 and regulation of cardiac myofilament function.

The results demonstrate the importance of PKC-mediated phosphorylation of cTnI S43/S45 in the control of myofilament activation and cross-bridge cycling rate and differential effects of agonists between WT and TGMyofilaments and within the TG my ofilaments.

Influence of isoproterenol and ouabain on excitation-contraction coupling, cross-bridge function, and energetics in failing human myocardium.

Major differences between the effects of isoproterenol and ouabain in failing human myocardium are related to calcium cycling with secondary effects on myocardial energetics.

Integration of pathways that signal cardiac growth with modulation of myofilament activity

Evidence argues strongly for a path of communication between the intrinsic functional changes associated with a sarcomeric protein mutation and nuclear events that are essential to the transduction of extrinsic signals leading to hypertrophy and failure.

Altered Myocardial Thin-Filament Function in the Failing Dahl Salt-Sensitive Rat Heart: Amelioration by Endothelin Blockade

The thin filament is a key modulator of contractile performance in the transition to failure in the Dahl salt-sensitive rat model and the alteration in thin-filament function may be mediated by an endothelin-triggered pathway potentially affecting protein kinase C signaling.

Neurohormonal systems during progression of heart failure: a review.

This article will review the key neuroh hormonal systems and their importance in heart failure on the basis of the current literature and suggest that neurohormonal activation over an extended period of time might be harmful to patients with chronic congestive heart failure.