title: A-kinase anchoring protein-Lbc promotes pro-fibrotic signaling in cardiac fibroblasts.
abstract: In response to stress or injury the heart undergoes an adverse remodeling process associated with cardiomyocyte hypertrophy and fibrosis. Transformation of cardiac fibroblasts to myofibroblasts is a crucial event initiating the fibrotic process. Cardiac myofibroblasts invade the myocardium and secrete excess amounts of extracellular matrix proteins, which cause myocardial stiffening, cardiac dysfunctions and progression to heart failure. While several studies indicate that the small GTPase RhoA can promote profibrotic responses, the exchange factors that modulate its activity in cardiac fibroblasts are yet to be identified. In the present study, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor (GEF) activity, is critical for activating RhoA and transducing profibrotic signals downstream of type I angiotensin II receptors (AT1Rs) in cardiac fibroblasts. In particular, our results indicate that suppression of AKAP-Lbc expression by infecting adult rat ventricular fibroblasts with lentiviruses encoding AKAP-Lbc specific short hairpin (sh) RNAs strongly reduces the ability of angiotensin II to promote RhoA activation, differentiation of cardiac fibroblasts to myofibroblasts, collagen deposition as well as myofibroblast migration. Interestingly, AT1Rs promote AKAP-Lbc activation via a pathway that requires the α subunit of the heterotrimeric G protein G12. These findings identify AKAP-Lbc as a key Rho-guanine nucleotide exchange factor modulating profibrotic responses in cardiac fibroblasts.
authors.affiliation: Department of Pharmacology and Toxicology, Faculté de Biologie et Médecine, University of Lausanne, 1005, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cavin
authors.affiliation: Department of Pharmacology and Toxicology, Faculté de Biologie et Médecine, University of Lausanne, 1005, Switzerland.
authors.forename: Darko
authors.initials: D
authors.lastname: Maric
authors.affiliation: Department of Pharmacology and Toxicology, Faculté de Biologie et Médecine, University of Lausanne, 1005, Switzerland. Electronic address: Dario.diviani@unil.ch.
authors.forename: Dario
authors.initials: D
authors.lastname: Diviani
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology*; D015778:Minor Histocompatibility Antigens; D008954:Models, Biological; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D000199:Actins; D000804:Angiotensin II; D003094:Collagen; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D015778:Minor Histocompatibility Antigens; D053773:Transforming Growth Factor beta1; D020742:rhoA GTP-Binding Protein; C586982:Akap13 protein, rat; C498862:Acta2 protein, rat
keywords: A kinase-anchoring protein (AKAP); A-kinase anchoring protein; AKAP; AT(1)Rs; AVF; Ang II; Cardiac fibroblast; ECM; G protein-coupled receptor; GEF; GTP; MRTF; NVM; Protein kinase A; RhoA; TGF-β; adult ventricular fibroblast; angiotensin II; extracellular matrix; guanine nucleotide exchange factor; guanosine triphosphate; myocardin related transcription factor; neonatal ventricular myocyte; sh; short hairpin; transforming growth factor β; type I angiotensin II receptors; α-SMA; α-smooth muscle actin; α1-ARs; α1-adrenergic receptors