Matrix metalloproteinase activation in heart failure due to volume-overloa and the effect of AT|1 receptor blockade

Abstract

In the present study, we have investigated the role of matrix metalloproteinases (MMP) during the development of volume overload induced moderate heart failure. Furthermore, we have tested whether the renin angiotensin system (RAS) or specifically the activation of AT1 receptors is involved in the progression to cardiac hypertrophy and heart failure caused by volume overload. This was achieved by the use of losartan, an AT1 receptor antagonist. Surgically induced aorto-venous fistula (AV shunt: AVF) is the model of volume overloaded heart failure used in these investigations. Animals were divided into three groups; a sham-operated control group, an AV shunt group and an AV shunt group treated with losartan. Hemodynamic and anatomical studies were performed at 8 weeks after the shunt surgery while all other studies were performed at 1 and 8 week post AV shunt induction. To examine whether MMP and MMP inhibitory protein (TIMP) activities are altered in this model of heart failure, zymography and reverse zymography were performed respectively using ventricular tissue samples. Immunoreactive MMP protein abundance was determined by Western blot analysis. To evaluate the role of angiotensin II, AT1 antagonism was applied to experimental animals (losartan:40 mg/kg/day). (Abstract shortened by UMI.)