Key result
Computational model shows disrupted DAG signaling after massive MI drives prolonged PKCα activation.
Why the study?
PKCα activity increases during heart failure despite up-regulation of a molecular braking mechanism, and it remained unclear how this increased activity is maintained.
A novel computational model elucidates the mechanism by which DAG homeostasis is disrupted during heart failure, resulting in prolonged PKCα activation despite molecular braking mechanisms.
Hypothesis-generating for DAG-PKCα targeting post-MI; extends computational models but requires in vivo validation before clinical consideration.
Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the β-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C α (PKCα) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKCα activity has been observed to increase during HF. This increase in PKCα activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism. Objective: I aim to explore how PKCα activity can be increased and maintained during HF despite the presence of a molecular braking mechanism. Methods and Results: Using a computational approach, I show that the local diacylglycerol (DAG) signaling is regulated through a two-compartment signaling system in cardiomyocytes. These results imply that after massive myocardial infarction (MI), local homeostasis of DAG signaling is disrupted. The loss of this balance leads to prolonged activation of PKCα, a key molecular target linked to LV remodeling and dysfunctional filling and ejection in the mammalian heart. This study also proposes an explanation for how DAG homeostasis is regulated during normal systolic and diastolic cardiac function. Conclusions: I developed a novel two-compartment computational model for regulating DAG homeostasis during Ang II-induced heart failure. This model provides a promising tool with which to study mechanisms of DAG signaling regulation during heart failure. The model can also aid in identification of novel therapeutic targets with the aim of improving the quality of life for heart failure patients.
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Naveed Aslam (2020) studied Heart failure. Computational model was evaluated on DAG signaling regulation and PKCα activity. A novel two-compartment computational model demonstrated that disruption of local diacylglycerol signaling homeostasis after massive myocardial infarction leads to prolonged activation of PKCα.
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