Abstract
Heart failure is a lethal disease that can develop after myocardial infarction, hypertension, or anticancer therapy. In the damaged heart, loss of function is mainly due to cardiomyocyte death and associated cardiac remodeling and fibrosis. In this context, A-kinase anchoring proteins (AKAPs) constitute a family of scaffolding proteins that facilitate the spatiotemporal activation of the cyclic adenosine monophosphate (AMP)-dependent protein kinase (PKA) and other transduction enzymes involved in cardiac remodeling. AKAP-Lbc, a cardiac enriched anchoring protein, has been shown to act as a key coordinator of the activity of signaling pathways involved in cardiac protection and remodeling. This review will summarize and discuss recent advances highlighting the role of the AKAP-Lbc signalosome in orchestrating adaptive responses in the stressed heart.
Highlights
The heart responds to various stresses and insults such as increased blood pressure, myocardial infarction, and exposure to drugs and toxicants by undergoing a remodeling process that leads to heart failure, a lethal condition in which the cardiac output cannot satisfy the oxygen needs of the body [1,2,3]
Initial in vitro studies performed in primary cultures of rat neonatal cardiomyocytes (NVMs) indicated that A-kinase anchoring proteins (AKAPs)-Lbc acts as a mediator of the hypertrophic effects induced by α1-adrenergic receptors (α1-ARs) and endothelin 1 receptor (ET1-R) agonists [57,59]
While a number of studies have highlighted the protective role of AKAP-Lbc during the compensated hypertrophic growth of the heart induced by pressure overload and neurohumoral stress, it is currently not known whether this anchoring protein is involved in later phases of cardiac remodeling
Summary
The heart responds to various stresses and insults such as increased blood pressure, myocardial infarction, and exposure to drugs and toxicants by undergoing a remodeling process that leads to heart failure, a lethal condition in which the cardiac output cannot satisfy the oxygen needs of the body [1,2,3]. About 17 AKAPs have been identified in cardiac tissues [21,22,23] and shown to regulate various homeostatic, adaptive as well as pathophysiological functions including heart rhythm and action potential propagation, calcium cycling and cardiac contraction, cardiac remodeling and heart failure, as well as cardiac protection [5,24,25,26] This suggests that modulating the ability of AKAP complexes to locally coordinate the activity of signaling molecules might have major impact on the function of the stressed and/or diseased heart and could be exploited to promote protection and maintain cardiac function. PKA reduces detrimental cardiac remodeling by protecting cardiomyocytes from dysfunction and death and by inhibiting cardiac fibrosis In this respect, it has been recently shown that activation of PKA signaling by prostaglandin E2 receptor 4 (EP4) agonists significantly prevented progression of myocardial fibrosis in response to pressure overload [53]. Several studies adopt more targeted approaches and investigate the function of individual AKAP-PKA signaling complexes in specific cardiac cellular populations
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