Cellular Retinoic Acid Binding Protein-I as a Drugable Target to Dampen Calcium-Calmodulin Dependent Protein Kinase II Activity

Abstract

Heart failure is the leading cause of death in developed countries. Current therapeutic approaches target the autonomic nervous system’s β and α adrenergic receptors to rescue the failing heart. Despite these approaches, heart failure is responsible for 600,000 deaths in the U.S as of 2004. For this reason new drugs need to be developed. Over the past 10 years, mounting evidence has identified Ca2+-calmodulin dependent protein kinase-II delta (CaMKII-δ) over activation as a main culprit in heart failure, but no groups have been able to develop a strategy to decrease this over activation. In this current study cellular retinoic acid binding protein I (Crabp-I) is shown to be a viable drugable target to dampen the activation of CaMKII-δ. Furthermore, using in vitro phosphorylation, western blot and qPCR assays, a novel retinoid analog (compound 11) has been shown to selectively mitigate CaMKII-δ induced hypertrophic damage. This current study sets the tone for the development of a new family of cardiovascular drugs that could help in decreasing the morbidity of heart failure.