Cyclic Nucleotides Signaling (Second Messengers) and Control of Myocardial Function: Effects of Heart Failure

Marı́n-Garcı́a, José

doi:10.1007/978-1-60761-147-9_8

Cited by 4 publications

(9 citation statements)

References 89 publications

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“…4, 5, and S9). Such coupling between PDE isoenzymes may be an important mechanism in stabilizing cAMP dynamics in the heart [11,13,74], including disease settings where alterations in isoenzyme-specific PDE expression and/or activity have been implicated [8,10–13,21,74–76]. Modeling results show that the ability of PDE2 to compensate for reduced activity of PDE4 is particularly strong.…”

Section: Discussionmentioning

confidence: 99%

“…Ablation of specific PDE activities through pharmacological inhibition or gene depletion is observed to promote cardiac apoptosis [7], accelerates development of heart failure (HF) [8] and increases likelihood of cardiac arrhythmias [8,9]. The importance of delicate regulation by distinct PDE families is also reflected by their isoform-specific alternations in cardiac diseases [8,10–13]. As examples, PDE2 upregulation in the failing heart is observed to attenuate β-adrenergic signaling [12], decreased PDE3 activity promotes cardiac myocyte apoptosis [10], and PDE4 downregulation is associated with arrhythmias in cardiac hypertrophy and HF [8].…”

Section: Introductionmentioning

confidence: 99%

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Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Zhao

Greenstein

Winslow

2015

Journal of Molecular and Cellular Cardiology

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In cardiac myocytes, the second messenger cAMP is synthesized within the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of multiple target proteins that are functionally critical to cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase isoenzymes (PDEs). The nature of the interactions between cGMP and the PDEs, as well as between PDE isoforms, and how these ultimately transduce the cGMP signal to regulate cAMP remains unclear. To better understand this, we have developed mechanistically detailed models of PDEs 1–4, the primary cAMP-hydrolyzing PDEs in cardiac myocytes, and integrated them into a model of the β-adrenergic signaling pathway. The PDE models are based on experimental studies performed on purified PDEs which have demonstrated that cAMP and cGMP bind competitively to the cyclic nucleotide (cN)-binding domains of PDEs 1, 2, and 3, while PDE4 regulation occurs via PKA-mediated phosphorylation. Individual PDE models reproduce experimentally measured cAMP hydrolysis rates with dose-dependent cGMP regulation. The fully integrated model replicates experimentally observed whole-cell cAMP activation-response relationships and temporal dynamics upon varying degrees of β-adrenergic stimulation in cardiac myocytes. Simulations reveal that as a result of network interactions, reduction in the level of one PDE is partially compensated for by increased activation of others. PDE2 and PDE4 exert the strongest compensatory roles among all PDEs. In addition, PDE2 competes with other PDEs to bind and hydrolyze cAMP and is a strong regulator of PDE interactions. Finally, an increasing level of cGMP gradually out-competes cAMP for the catalytic sites of PDEs 1, 2, and 3, suppresses their cAMP hydrolysis rates, and results in amplified cAMP signaling. These results provide insights into how PDEs transduce cGMP signals to regulate cAMP and how PDE interactions affect cardiac β-adrenergic response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Zhao

Greenstein

Winslow

2015

Journal of Molecular and Cellular Cardiology

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“…Balanced signaling between cAMP and cGMP is crucial in maintaining normal cardiac function, especially when prominent remodeling of the cN signaling network is also observed in cardiac hypertrophy and heart failure, potentially contributing to altered and/or untargeted cN signals, aberrant phosphorylation of target proteins, and cardiac dysfunction [22–26]. However, relatively little is known about the ways in which different PDE isoforms regulate the cN cross-talk that enables communication between the β-adrenergic and NO/cGMP/PKG pathways.…”

Section: Discussionmentioning

confidence: 99%

“…These results reflect that redundancy of the PDEs in the cN signaling network contributes a degree of robustness to perturbations. This compensatory coupling between PDEs may be an important mechanism in controlling cN dynamics in the heart [17, 22, 69], including disease settings where alterations in isoenzyme-specific PDE expression and/or activity have been implicated [17, 22, 69–79]. …”

Section: Discussionmentioning

confidence: 99%

“…It is known that stimulation of the β-adrenergic and NO/cGMP/PKG pathways exert opposing physiological responses, with the former enhancing cardiac inotropy and lusitropy [7, 8] and the latter attenuating cardiac contractility [9–13] and antagonizing β-adrenergic tone [4–6, 14–21]. Furthermore, many signaling components in the network are perturbed in cardiac hypertrophy and heart failure (HF), potentially contributing to disease remodeling [22–26]. As a result, it is important to understand the regulatory mechanisms that maintain balance between the cN signals in both health and disease.…”

Section: Introductionmentioning

confidence: 99%

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Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network

Zhao

Greenstein

Winslow

2016

Journal of Molecular and Cellular Cardiology

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The balanced signaling between the two cyclic nucleotides (cNs) cAMP and cGMP plays a critical role in regulating cardiac contractility. Their degradation is controlled by distinctly regulated phosphodiesterase isoenzymes (PDEs), which in turn are also regulated by these cNs. As a result, PDEs facilitate communication between the β-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP respectively. The phenomena in which the cAMP and cGMP pathways influence the dynamics of each other are collectively referred to as cN cross-talk. However, the cross-talk response and the individual roles of each PDE isoenzyme in shaping this response remain to be fully characterized. We have developed a computational model of the cN cross-talk network that mechanistically integrates the β-adrenergic and NO/cGMP/PKG pathways via regulation of PDEs by both cNs. The individual model components and the integrated network model replicate experimentally observed activation-response relationships and temporal dynamics. The model predicts that, due to compensatory interactions between PDEs, NO stimulation in the presence of sub-maximal β-adrenergic stimulation results in an increase in cytosolic cAMP accumulation and corresponding increases in PKA-I and PKA-II activation; however, the potentiation is small in magnitude compared to that of NO activation of the NO/cGMP/PKG pathway. In a reciprocal manner, β-adrenergic stimulation in the presence of sub-maximal NO stimulation results in modest cGMP elevation and corresponding increase in PKG activation. In addition, we demonstrate that PDE2 hydrolyzes increasing amounts of cAMP with increasing levels of β-adrenergic stimulation, and hydrolyzes increasing amounts of cGMP with decreasing levels of NO stimulation. Finally, we show that PDE2 compensates for inhibition of PDE5 both in terms of cGMP and cAMP dynamics, leading to cGMP elevation and increased PKG activation, while maintaining whole-cell β-adrenergic responses similar to that prior to PDE5 inhibition. By defining and quantifying reactions comprising cN cross-talk, the model characterizes the crosstalk response and reveals the underlying mechanisms of PDEs in this non-linear, tightly-coupled reaction system.

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Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes

Zhao

2017

Microdomains in the Cardiovascular System

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Cyclic Nucleotides Signaling (Second Messengers) and Control of Myocardial Function: Effects of Heart Failure

Cited by 4 publications

References 89 publications

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway

Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network

Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes

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