How the activity of PKCα is increased and maintained in Heart Failure despite the up‐regulation of molecular braking mechanism?

Heart failure (HF) disease is marked by dampened cardiac contractility. A milder target which could improve the contractile function without desensitization of β‐Adregenric system may help during HF condition and potentially improve survival. It seems that inhibition of PKCα activity might fit this criterion of a milder therapeutic target to boost contractility for HF patients. Observations show that PKCα activity is increased during HF disease. This seems to be bizarre as the increase in PKCα activity is also accompanied by up‐regulation of a molecular braking mechanism. Here, we explore the question that how PKCα activity can be increased and maintained during HF despite the presence of molecular brakes? More specifically, we investigate the possibility of a positive feedback loop through which PKCα might sustain its activity in heart disease condition. Through a computational approach we show that PKCα activity in cardiomyocytes is regulated through a local DAG signaling system. Our results also show that local DAG cascade is regulated through a two compartment signaling system. Our results imply that after large MI local homeostasis of DAG is disrupted and the loss of this balance leads to prolonged activation of PKCα, a key molecular target linked with LV remodeling and dysfunctional filling and ejection characteristics in mammalian heart. This study also proposes an explanation for how the DAG homeostasis is regulated during normal systolic and diastolic functions? Support or Funding Information Privately funded