title: A novel player in cellular hypertrophy: Giβγ/PI3K-dependent activation of the RacGEF TIAM-1 is required for α₁-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes.
abstract: Activation of α(1)-adrenoceptors (α(1)-AR) by high catecholamine levels, e.g. in heart failure, is thought to be a driving force of cardiac hypertrophy. In this context several downstream mediators and cascades have been identified to potentially play a role in cardiomyocyte hypertrophy. One of these proteins is the monomeric G protein Rac1. However, until now it is unclear how this essential G protein is activated by α(1)-AR agonists and what are the downstream targets inducing cellular growth. By using protein-based as well as pharmacological inhibitors and the shRNA technique, we demonstrate that in neonatal rat cardiomyocytes (NRCM) Rac1 is activated via a cascade involving the α(1A)-AR subtype, G(i)βγ, the phosphoinositide-3'-kinase and the guanine nucleotide exchange factor Tiam1. We further demonstrate that this signaling induces an increase in protein synthesis, cell size and atrial natriuretic peptide expression. We identified the p21-activated kinase 2 (PAK2) as a downstream effector of Rac1 and were able to link this cascade to the activation of the pro-hypertrophic kinases ERK1/2 and p90RSK. Our data thus reveal a prominent role of the α(1A)-AR/G(i)βγ/Tiam1-mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM.
authors.affiliation: Institute of Experimental Pharmacology and Toxicology, Medical Faculty Mannheim, Heidelberg University, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Vettel
authors.forename: Karola
authors.initials: K
authors.lastname: Wittig
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Christina M
authors.initials: CM
authors.lastname: Wuertz
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.forename: Susanne
authors.initials: S
authors.lastname: Lutz
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D015180:Electrophoresis, Gel, Two-Dimensional; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D054462:p21-Activated Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D000634:Aminoquinolines; D020662:Guanine Nucleotide Exchange Factors; C487513:NSC 23766; D009363:Neoplasm Proteins; D011743:Pyrimidines; D018340:Receptors, Adrenergic, alpha-1; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513259:Tiam1 protein, rat; D010656:Phenylephrine; D019869:Phosphatidylinositol 3-Kinases; C515910:Pak2 protein, rat; D054462:p21-Activated Kinases; C499134:Rac1 protein, rat; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020830:rac1 GTP-Binding Protein