Heart failure (HF) is characterised by a reduction in cardiac contractility. During heart failure, a mild treatment target that improves contractile function without desensitising the -adrenergic system could enhance cardiac contractility and possibly survival. Inhibiting the activity of protein kinase C (PKC) may meet the criteria for a therapeutic target with fewer systemic side effects while yet increasing contractility in HF patients. During HF, PKC activity has been reported to rise. The fact that this increase in PKC activity is accompanied by up-regulation of a molecular braking mechanism is confusing.
Despite the presence of a molecular braking mechanism, I want to see if PKC activity can be boosted and maintained during HF.
Methods and Results: I show that in cardiomyocytes, local diacylglycerol (DAG) signalling is regulated by a two-compartment signalling system using a computational approach. These findings suggest that local DAG signalling equilibrium is compromised after a severe myocardial infarction (MI). When this equilibrium is disrupted, PKC, a critical molecular target connected to LV remodelling and defective filling and ejection in mammals, is activated over an extended period of time. This research also explains how DAG homeostasis is maintained throughout normal systolic and diastolic heart activity.
Conclusions: During Ang II-induced heart failure, I devised an unique two-compartment computational model for regulating DAG homeostasis. This model could be used to investigate the mechanisms of DAG signalling control in heart failure. The model can also be used to find new therapeutic targets for heart failure patients, with the goal of enhancing their quality of life.
Author (S) Details
BioSystOmics 4424 Jim West Street, Bellaire, Texas 77401, USA.
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