Characterization of the role of Rho activating signaling complexes in G protein‐coupled receptor induced cardiac fibrosis

Among the profibrotic factors that are secreted in the myocardium in response to stress, GPCR agonist such as angiotensin II (AngII) has been shown to play a major role in mediating the cellular responses such as phenotypic transition of fibroblasts to myofibroblasts, extracellular matrix proteins production, cell proliferation and invasiveness that ultimately lead to fibrosis. While it has been reported that the small GTPase RhoA could be involved in profibrotic signalling initiated by AngII, the transduction pathways mediating RhoA activation in cardiac fibroblasts have not been identified. Here, we show that AKAP‐Lbc, a cardiac A‐kinase anchoring protein (AKAP) with an intrinsic Rho‐specific guanine nucleotide exchange factors (RhoGEF) activity, is expressed in cardiac fibroblasts and is critical for activating RhoA and transducing fibrotic signals downstream of angiotensin II receptor. This is shown by the fact that downregulation of AKAP‐Lbc in adult rat ventricular fibroblasts, by using lentivirus‐delivered shRNAs, impairs RhoA activation induced by AngII and the ability of cardiac fibroblasts to invade Matrigel. This work is supported by Fonds National Suisse de la Recherche Scientifique