Study on Increase in PKC\(\alpha\) Activity during Heart Failure Despite the Stimulation of PKC\(\alpha\) Braking Mechanism
Recent Research Advances in Biology Vol. 12,
30 July 2021
Rationale: Heart failure (HF) is marked by dampened cardiac contractility. A mild therapeutic target that improves contractile function without desensitizing the \(\alpha\)-adrenergic system during HF may improve cardiac contractility and potentially survival. Inhibiting protein kinase C \(\alpha\) (PKC\(\alpha\)) activity may fit the criteria of a therapeutic target with milder systemic effects that still boosts contractility in HF patients. PKC\(\alpha\) activity has been observed to increase during HF. This increase in PKC\(\alpha\) activity is perplexing because it is also accompanied by up-regulation of a molecular braking mechanism.
Objective: I aim to explore how PKC\(\alpha\) 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 PKC\(\alpha\), 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.
- Myocardial infarction
- contractile dysfunction
- \(\beta\)-adrenergic system desensitization
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