Abstract P144: Local Signaling And Cardiac Hypertrophy:specificity In The Face Of Pleiotropy

Abstract

Rationale: Most likely, the overall myocyte cell growth during the pathological state of cardiac hypertrophy is regulated by a local muscle A-kinase anchoring protein β (mAKAPβ) complex. The mAKAPβ may act as a significant coordinator of myocyte hypertrophic signals. It may critically integrate the hypertrophic signals due to β-adrenergic and leukemia inhibitory factor (LIF)/gp-130 receptor stimulation. Observations suggest that mAKAPβ signalosome may act as a gate-keeper for regulating nuclear factor of activated T cells (NFATc) activity and nuclear localization of this complex might be directly linked to the induction of cardiac hypertrophy. The mAKAPβ complex might function through modulating the profiles of a local cyclic adenosine 3’,5’ monophosphate (cAMP) microdomain at perinuclear region in cardiomyocytes. The acute stimulation of cAMP may be beneficial for the heart, whereas chronic stimulation might cause damage. The transition between the chronic and acute function of cAMP is probably modulated by the ability of myocytes to tightly regulate the cAMP levels in local microdomains across the cell. Any dysfunction in this process may lead to net accumulation and a global rise of cAMP levels, leading to deleterious effects on the heart. Objective: cAMP is a single messenger but delivers multiple messages in myocytes. How is this managed? Here, we aim to investigate a key question that how mAKAPβ signalosome might ensure the microdomain specificity despite the pleiotropic nature of the second messenger. Methods and Results: Our results may explain how, in the context of hypertrophy, mAKAPβ complex coordinates the interactions between two coupled cAMP-induced feedback loops and LIF-induced activation of the MAPK pathway. Our results may also explain that mAKAPβ complex functions through anchoring protein kinase A (PKA) and ERK5 in the signalosome thus, modulating the bidirectional regulation of phosphodiesterase and hence the control of localized cAMP metabolism as well as the shape and temporal profile of the second messenger in a specific domain. Conclusion: Here, we propose a mechanistic model which suggests that stress-induced reprofiling of cAMP flux at discrete cellular locations may lead to cardiovascular disease.