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

Abstract

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.

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

“…Phosphodiesterase‐5A inhibitors block one of the main regulator of cGMP degradation thereby preserving and/or increasing intracellular cGMP concentration 4. Theoretically, blocking the PDE5A in pathological LV remodelling could provide a useful tool in the management of HF patients.…”

“…The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) axis has been described as an important regulator of cardiac contractility 4. In brief, under physiological conditions NO is produced by the endothelial cells and activates sGC as a gaseous transmitter in its target cells such as cardiomyocytes and vascular smooth muscle cells.…”

“…In brief, under physiological conditions NO is produced by the endothelial cells and activates sGC as a gaseous transmitter in its target cells such as cardiomyocytes and vascular smooth muscle cells. In response to this, sGC produces cGMP, the key regulator of the downstream effector PKG enzyme 4. Essential regulators of this system are the phosphodiesterases (PDEs) as they are able to degrade cGMP to 5′‐GMP 4.…”

“…In response to this, sGC produces cGMP, the key regulator of the downstream effector PKG enzyme 4. Essential regulators of this system are the phosphodiesterases (PDEs) as they are able to degrade cGMP to 5′‐GMP 4. Phosphodiesterase‐5A (PDE5A) is specific for cGMP molecules4 and has been described to be upregulated in different types of HF and in diabetic cardiomyopathy in particular 5, 6.…”

“…Essential regulators of this system are the phosphodiesterases (PDEs) as they are able to degrade cGMP to 5′‐GMP 4. Phosphodiesterase‐5A (PDE5A) is specific for cGMP molecules4 and has been described to be upregulated in different types of HF and in diabetic cardiomyopathy in particular 5, 6. Theoretically, the above‐mentioned upregulation of PDEs coupled with the enhanced nitro‐oxidative stress3 could notably contribute to the impaired cGMP–PKG signalling in the myocardium of HFpEF patients 7, 8…”