title: Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice.
abstract: Hypertrophy is a critical event in the onset of failure in chronically overloaded hearts. Focal adhesion kinase (FAK) has attracted particular attention as a mediator of hypertrophy induced by increased load. Here, we demonstrate increased expression and phosphorylation of FAK in the hypertrophic left ventricles (LVs) of aortic-banded mice. We used an RNA interference strategy to examine whether FAK signaling plays a role in the pathophysiology of load-induced LV hypertrophy and failure. Intrajugular delivery of specific small interfering RNA induced prolonged FAK silencing ( approximately 70%) in both normal and hypertrophic LVs. Myocardial FAK silencing was accompanied by prevention, as well as reversal, of load-induced left ventricular hypertrophy. The function of LVs was preserved and the survival rate was higher in banded mice treated with small interfering RNA targeted to FAK, despite the persistent pressure overload. Studies in cardiac myocytes and fibroblasts harvested from LVs confirmed the ability of the systemically administered specific small interfering RNA to silence FAK in both cell types. Further analysis indicated attenuation of cardiac myocyte hypertrophic growth and of the rise in the expression of beta-myosin heavy chain in overloaded LVs. Moreover, FAK silencing was demonstrated to attenuate the rise in the fibrosis, collagen content, and activity of matrix metalloproteinase-2 in overloaded LVs, as well as the rise of matrix metalloproteinase-2 protein expression in fibroblasts harvested from overloaded LVs. This study provides novel evidence that FAK may be involved in multiple aspects of the pathophysiology of cardiac hypertrophy and failure induced by pressure overload.
authors.affiliation: Department of Internal Medicine, School of Medicine, State University of Campinas, Sao Paulo, Brazil.
authors.forename: Carolina F M Z
authors.initials: CF
authors.lastname: Clemente
authors.forename: Thais F
authors.initials: TF
authors.lastname: Tornatore
authors.forename: Thais H
authors.initials: TH
authors.lastname: Theizen
authors.forename: Ana C
authors.initials: AC
authors.lastname: Deckmann
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Pereira
authors.forename: Iscia
authors.initials: I
authors.lastname: Lopes-Cendes
authors.forename: José Roberto M
authors.initials: JR
authors.lastname: Souza
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018390:Gene Targeting / Q000379:methods*; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse