560 Differential activation of natriuretic peptides in human heart failure and relationship to cardiac function: evidence for peptide deficiency

ABSTRACT Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired β-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of β-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.

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Natriuretic Peptides and MicroRNAs 155 And 425 in Human Heart Failure: Biomarker Roles and Pathophysiologic Regulation

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2020.09.058 ◽

2020 ◽

Vol 26 (10) ◽

pp. S18

Author(s):

Yang Chen ◽

Xiao Ma ◽

Seethalakshmi Iyer ◽

Shawn Reginauld ◽

John Burnett

Keyword(s):

Heart Failure ◽

Natriuretic Peptides ◽

Human Heart ◽

Human Heart Failure

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A polymorphism within a conserved beta1-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0509937103 ◽

2006 ◽

Vol 103 (30) ◽

pp. 11288-11293 ◽

Cited By ~ 352

Author(s):

S. B. Liggett ◽

J. Mialet-Perez ◽

S. Thaneemit-Chen ◽

S. A. Weber ◽

S. M. Greene ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Beta Blocker ◽

Adrenergic Receptor ◽

Human Heart ◽

Human Heart Failure

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Chemotherapeutic cardiotoxicity is associated with elevated β1-adrenergic receptor density

10.1101/2020.09.17.301689 ◽

2020 ◽

Author(s):

Manveen K Gupta ◽

Elizabeth E. Martelli ◽

Kate T. Stenson ◽

Sathyamangla V. Naga Prasad

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Function ◽

Heart Failure Patient ◽

Adrenergic Receptors ◽

Human Heart ◽

Human Heart Failure ◽

Anthracycline Cardiotoxicity ◽

End Stage ◽

Selective Increase

AbstractObjectiveTo understand the underlying pathways that promote cardiotoxicity following chemotherapy.BackgroundAnthracyclines are associated with cardiotoxicity which could be potentiated with use of complementary agents (like anti-ERBB2 inhibitors) which together afford robust anti-neoplastic effects. Anthracyclines lead to oxidative stress and thought to induce cardiotoxicity. However, interventions reducing oxidative stress in patients have been unsuccessful suggesting mechanisms beyond oxidative stress. Despite β-adrenergic receptors (βARs) being key regulators of cardiac function, nothing is known about their role in chemotherapy-mediated cardiotoxicity.Methodsβ1 and/or β2-AR density was assessed in end-stage human heart failure patient samples either due to anthracycline cardiotoxicity or non-anthracycline dilated cardiomyopathy (DCM). Since ERBB2 inhibition is integral to overall chemotherapeutic arsenal, we assessed β1- and/or β2-AR density, cardiac function by echocardiography and immunohistochemistry in mice following ERBB2-specific inhibitor AG825.ResultsSelective increase in cardiac β1AR density is observed in end-stage human heart failure patient samples due to anthracycline cardiotoxicity as well as in ERBB2 inhibitor-treated mice.ConclusionsElevated β1AR density may be the key common underlying mechanism which is altered in response to chemotherapy promoting cardiac dilation of otherwise healthy hearts.HighlightsIn contrast to downregulation of β1-adrenergic receptors (β1AR) in end-stage human heart failure, anthracycline cardiotoxicity-mediated failure is associated with selective increase in β1AR density.ERBB2 inhibitor (AG825) treatment in mice results in cardiac dilation and selective rise in β1AR density showing that increased β1AR density in the heart could be a common mechanism underlying cardiotoxicity.

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