How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency

Abstract

Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.

cGMP signaling: probing antagonistic cyclic nucleotide platelet signals by modeling and experiment

“…As a result, we have that based on the data our model cannot be rejected (subsequently shown) and thus the model, in particular the topology of the interaction network, with the fitted parameters can be used as an explanation for the experiment investigating the connection between cGMP turnover and drug concentration for platelets. Furthermore it is reasonable to use the model for further in silico investigations, for example with the optimization framework presented in Breitenbach et al (2019a,b) for optimal dosage calculations or for finding most effective drug combinations in silico .…”

“…Once the model is set up and describes the data curves sufficiently well, i.e. the model cannot be rejected, we can further exploit the information coded in the fitted mathematical model by an optimization framework presented in Breitenbach et al (2019a,b) in order to calculate an optimal drug dosage or most effective drug combinations for a desired cGMP concentration or for steering the concentration time-resolved along a desired cGMP concentration curve.…”

“…A further application of our model is that the cGMP levels can be calculated by the VASP levels. Once the VASP levels are given the optimization framework in Breitenbach et al (2019a,b) can be used to calculate the cGMP level such that the predicted VASP level fits optimally to the given VASP levels. In this optimization scenario, the cGMP levels are defined as external stimuli that cause a corresponding VASP level.…”

Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

“…The occurrence and development of cardiac hypertrophy is also accompanied by the abnormal activation of a large number of important signaling pathways ( 5 , 39 , 40 ). Consequently, there is an increased level of interest in how key signaling pathways participate in the epigenetic regulation of cardiac hypertrophy ( 41 , 42 ). Our previous studies found that an imbalance of histone acetylation modification is involved in PE-induced hypertrophy in cardiomyocytes, and that an HAT inhibitor, AA, can attenuate PE-induced cardiomyocyte hypertrophy ( 4 ); however, the relevant upstream signaling pathways have yet to be identified.…”

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

“…However, these approaches will always be necessary because of the simplified process established in a largely isolated system and temporal relationships. More recently, a new method, known as mathematical optimization framework, also analyzed the complex ERK1/2 cascade in cardiomyocytes to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth [19].…”