Gender Differences in Tumor Necrosis Factor‐α Mediated Ventricular Dilatation

Myocardial levels of TNF‐α are acutely elevated in males in the aortocaval fistula heart failure model. This prompted us to test the hypothesis that TNF mediates marked reductions in cardiomyocyte adhesion, thereby producing left ventricular (LV) dilatation. Accordingly, LV pressure‐volume relationships were obtained in functioning hearts prior to (baseline) and 30 minutes after beginning a sustained TNF infusion. The effect of TNF (0 or 50 ng/ml)on adhesion to laminin was also determined in isolated adult cardiomyocytes obtained from normal and ovariectomized (OX) females. Isolated cardiomyocytes were also pretreated with the Src kinase inhibitor, PP2. Exposure to TNF rapidly induced LV dilatation similar to that produced by inactivation of β1 integrin mediated adhesion. The decrease in cardiomyocyte adhesion in the TNF treated cells (42%; P<0.001) was reversed by the Src kinase inhibitor. In contrast, the marked decrease in adhesion seen in the OX group was not exacerbated by TNF exposure. In addition, TNF induced significant Src kinase activation, reflected by a 30% increase in Y418 phosphorylation. The central finding of this study is TNF produces a marked decrease in adult cardiomyocyte adhesion via induction of Src kinase, indicative of TNF induced reductions in cardiomyocyte adhesion in male and OX female hearts being a novel mechanism producing LV dilatation. NIH grant HL073990