Involvement of the MEKK1 signaling pathway in the regulation of epicardial cell behavior by hyaluronan

Abstract

During embryonic development, cells comprising the outermost layer of the heart or epicardium play a critical role in the formation of the coronary vasculature. Thus, uncovering the molecular mechanisms that govern epicardial cell behavior is imperative to better understand the etiology of cardiovascular diseases. In this study, we investigated the function of hyaluronan (HA), a major component of the extracellular matrix, in the modulation of epicardial signaling. We show that stimulation of epicardial cells with high molecular weight HA (HMW-HA) promotes the association of MEKK1 with the HA receptor CD44 and induces MEKK1 phosphorylation. This leads to the activation of two distinct pathways, one ERK-dependent and another NFκB-dependent. Furthermore, HMW-HA stimulates epicardial cells to differentiate and invade, as suggested by increased vimentin expression and enhanced invasion through a collagen matrix. Blockade of CD44, transfection with a kinase inactive MEKK1 construct or the use of ERK1/2 and NFκB inhibitors significantly abrogates the invasive response to HMW-HA. Together, these findings suggest an important role for HA in the regulation of epicardial cell fate via activation of MEKK1 signaling cascades.

Resident cardiac progenitor cells: At the heart of regeneration

“…Activation of the prokineticin receptor (PKR1), results in secretion of its ligand, PK2, by cardiomyocytes, to act on EPDCs, augmenting their proliferation which induces neovascularization in transgenic mice overexpressing PRK1 [93]. High molecular weight hyaluronan has been shown to stimulate migration and differentiation of epicardial cells in vitro [94]. Whether either of these stimuli can be translated into the adult heart for activation of EPDCs remains to be investigated.…”

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