title: Small interfering RNA targeting focal adhesion kinase prevents cardiac dysfunction in endotoxemia.
abstract: Sepsis and septic shock are associated with cardiac depression. Cardiovascular instability is a major cause of death in patients with sepsis. Focal adhesion kinase (FAK) is a potential mediator of cardiomyocyte responses to oxidative and mechanical stress. Myocardial collagen deposition can affect cardiac compliance and contractility. The aim of the present study was to determine whether the silencing of FAK is protective against endotoxemia-induced alterations of cardiac structure and function. In male Wistar rats, endotoxemia was induced by intraperitoneal injection of lipopolysaccharide (10 mg/kg). Cardiac morphometry and function were studied in vivo by left ventricular catheterization and histology. Intravenous injection of small interfering RNA targeting FAK was used to silence myocardial expression of the kinase. The hearts of lipopolysaccharide-injected rats showed collagen deposition, increased matrix metalloproteinase 2 activity, and myocyte hypertrophy, as well as reduced 24-h +dP/dt and -dP/dt, together with hypotension, increased left ventricular end-diastolic pressure, and elevated levels of FAK (phosphorylated and unphosphorylated). Focal adhesion kinase silencing reduced the expression and activation of the kinase in cardiac tissue, as well as protecting against the increased collagen deposition, greater matrix metalloproteinase 2 activity, and reduced cardiac contractility that occur during endotoxemia. In conclusion, FAK is activated in endotoxemia, playing a role in cardiac remodeling and in the impairment of cardiac function. This kinase represents a potential therapeutic target for the protection of cardiac function in patients with sepsis.
authors.affiliation: Department of Emergency Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Guido
authors.forename: Carolina F
authors.initials: CF
authors.lastname: Clemente
authors.forename: Ana I
authors.initials: AI
authors.lastname: Moretti
authors.forename: Hermes V
authors.initials: HV
authors.lastname: Barbeiro
authors.forename: Victor
authors.initials: V
authors.lastname: Debbas
authors.forename: Elia G
authors.initials: EG
authors.lastname: Caldini
authors.forename: Kleber G
authors.initials: KG
authors.lastname: Franchini
authors.forename: Francisco G
authors.initials: FG
authors.lastname: Soriano
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008070:Lipopolysaccharides; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D003094:Collagen; D051417:Focal Adhesion Kinase 1; C496052:Ptk2 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat