Targeted disruption of ICAM-1, P-selectin genes improves cardiac function and survival in TNF-alpha transgenic mice

We have developed a transgenic mouse model in which tumor necrosis factor ( TNF)-alpha is overexpressed exclusively in the heart under the regulation o f the alpha- myosin heavy chain promoter. These animals develop chronic hea rt failure associated with severe leukocyte infiltration in both the atria and the ventricles. The purpose of this study was to investigate the role o f adhesion molecules in mediating cardiac dysfunction in the TNF-alpha tran sgenic model. TNF-alpha transgenic mice were bred with mice null for interc ellular adhesion molecule (ICAM)- 1 and P- selectin genes to obtain a linea ge of ICAM- 1 and P- selectin null mice with selective overexpression of TN F-alpha in the heart. TNF-alpha transgenic animals showed marked upregulati on of ICAM- 1 mRNA and protein; however, P- selectin mRNA and protein remai ned undetectable despite chronic TNF overexpression. Cardiac function was m arkedly improved in the ICAM-1 (-/-), P- selectin (-/-), TNF-alpha transgen ic group versus the ICAM (+/+), P-selectin (+/+), TNF-alpha transgenic grou p. Kaplan- Meier survival curves showed statistically significant prolonged survival in the ICAM-1 (-/-), P-selectin (-/-), TNF-alpha transgenic anima ls. These data suggest that ICAM-1 mediates at least in part the cardiac dy sfunction induced by TNF-alpha expression by cardiac myocytes.