Search

Received 21 Jun 2011; first review completed 28 Jun 2011; accepted in final form 11 Aug 2011ABSTRACT—Sepsis and septic shock are associated with cardiac depression. Cardiovascular instability is a major causeof death in patients with sepsis. Focal adhesion kinase (FAK) is a potential mediator of cardiomyocyte responses tooxidative and mechanical stress. Myocardial collagen deposition can affect cardiac compliance and contractility. The aimof the present study was to determine whether the silencing of FAK is protective against endotoxemia-induced alterationsof cardiac structure and function. In male Wistar rats, endotoxemia was induced by intraperitoneal injection oflipopolysaccharide (10 mg/kg). Cardiac morphometry and function were studied in vivo by left ventricular catheterizationand histology. Intravenous injection of small interfering RNA targeting FAK was used to silence myocardial expression ofthe kinase. The hearts of lipopolysaccharide-injected rats showed collagen deposition, increased matrix metalloproteinase2 activity, and myocyte hypertrophy, as well as reduced 24-h +dP/dt and jdP/dt, together with hypotension, increased leftventricular end-diastolic pressure, and elevated levels of FAK (phosphorylated and unphosphorylated). Focal adhesionkinase silencing reduced the expression and activation of the kinase in cardiac tissue, as well as protecting against theincreased collagen deposition, greater matrix metalloproteinase 2 activity, and reduced cardiac contractility that occurduring endotoxemia. In conclusion, FAK is activated in endotoxemia, playing a role in cardiac remodeling and in theimpairment of cardiac function. This kinase represents a potential therapeutic target for the protection of cardiac function inpatients with sepsis.KEYWORDS—Focal adhesion protein-tyrosine kinases, cytokines, inflammation, sepsis, shock septic

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.