title: Myocardial Rac1 exhibits partial involvement in thyroxin-induced cardiomyocyte hypertrophy and its inhibition is not sufficient to improve cardiac dysfunction or contractile abnormalities in mouse papillary muscles.
abstract: : Development of cardiac hypertrophy after thyroxin (T4) treatment is well recognized. Recently, we observed that T4-induced cardiac hypertrophy is associated with increased cardiac Rac1 expression and activity. Whether this Rac1 increase has a role in inducing this cardiac phenotype is, however, still unknown. Here, we showed that T4 treatment (500 µg/kg/d) for 2 weeks resulted in increased myocardial Rac1 activity with subsequent hypertension, cardiac hypertrophy, and left ventricular systolic dysfunction in vivo. Isolated right ventricular papillary muscles of T4-treated mice maintained their peak isometric active developed tension but exhibited significant decreases in their corresponding time to peak and in relaxation times. Positive inotropic responses to increasing pacing rate and β-adrenergic stimulation were also depressed in these muscles. Pravastatin (10 mg/kg/d), a Rac1 inhibitor, significantly decreased myocardial Rac1 activity, hypertension, and cardiomyocyte size in T4-treated mice but could not attenuate gross heart weight or functional cardiac changes in these mice. Our data showed that T4 could activate different signaling pathways with distinct cardiovascular outcomes. We also provide the first mechanistic evidence for the partial involvement of Rac1 activation in T4-induced cardiomyocyte hypertrophy and reveal a putative role for Rac1 in the development of T4-induced hypertension.
authors: Department of Physiology and Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, Ohio State University, Columbus, OH 43201, USA.
authors: Mohammad T
authors: MT
authors: Elnakish
authors: Leni
authors: L
authors: Moldovan
authors: Mahmood
authors: M
authors: Khan
authors: Hamdy H
authors: HH
authors: Hassanain
authors: Paul M L
authors: PM
authors: Janssen
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010210:Papillary Muscles / Q000503:physiopathology*; D017035:Pravastatin / Q000494:pharmacology; D013974:Thyroxine / Q000633:toxicity*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D017035:Pravastatin; D013974:Thyroxine