ANGIOTENSIN II-MEDIATED CARDIOMYOCYTE HYPERTROPHY DOES NOT REQUIRE BETA-ARRESTEV-DEPENDENT SIGNALLING OR SCAFFOLDING

摘要

Background: Angiotensin II (Ang II), a potent vasopeptide hormone required for blood pressure regulation, directly stimulates left ventricular hypertrophy by hijacking the growth machinery of the epidermal growth factor receptor (EGFR) to trigger ERK1/2 phosphorylation and transcriptional activation. Known as the 'triple membrane-passing signalling paradigm of EGFR transactivation', Ang II activation of its cognate G protein-coupled receptor (GPCR), the AT,R, leads to metalloprotease-dependent release of EGF-like ligands, such as HB-EGF, which are then able to bind extracellularly to the EGFR to activate growth. Classically associated with G protein-coupled receptor (GPCR) desensitisation and internalisation of activated receptors, beta-arrestins have emerged as mediators of growth pathway activation. Recent evidence posits that beta-arrestins can modulate downstream signalling pathways by acting as a scaffold for protein-protein interactions in a manner independent of G protein-mediated cascades. Of particular interest is the regulated, activation-dependent recruitment of mitogen-activated protein kinases, ERK1/2, which are known to play a role in cardiomyocyte hypertrophy in response to Ang II.