AKIP1 regulation of PKA and NF‐κB in the heart

Abstract

Ischemic preconditioning, an endogenous protective mechanism to salvage ischemic myocardium, was described nearly 25 years ago; however, there has been little to no clinical translation. Further, there has been a critical lack of knowledge to understand the molecular mechanisms that bring about the protection. Nuclear factor‐kappa B (NF‐κB) and protein kinase A (PKA) are key regulators of gene transcription in the heart and have contradictory roles in cell death and survival. Activation of NF‐κB and PKA has been shown to be protective as well as promote cardiac cell death in the setting of ischemia or oxidant stress. The answer as to why these two important regulators of gene transcription and cardiac physiology produce such a dichotomous response upon stress induction may provide insights into how protective signaling in the heart is integrated. We have discovered a novel scaffolding protein known as A‐kinase interacting protein 1 (AKIP1) that is expressed at low levels in the heart and is induced by stress. Our data shows that AKIP1 binds to and regulates nuclear localization of PKA catalytic subunit (PKAc) and increases nuclear PKAc activity. Further, AKIP1 interacts with and enhances NF‐κB nuclear localization in a PKAc dependent manner where disruption of AKIP1 binding to PKAc enhances nuclear NF‐κB. In cardiomyocytes and in the heart, oxidant/ischemic stress caused an increase of AKIP1 levels. Further, our data suggests that overexpression of AKIP1 was protective to the heart. Therefore, we infer that AKIP1 may be a key molecular regulator/scaffold that assembles PKAc and NF‐κB signaling complexes to alter the physiologic response of the heart in the basal and stressed states. Understanding the dynamics and physiologic implications of the interaction of PKAc and NF‐κB with AKIP1 may provide a novel therapeutic control point for limiting cardiac injury associated with ischemic stress.