Oxidative remodeling in pressure overload induced chronic heart failure

Despite extensive strides in understanding pressure overload induced heart failure, there is very little known about oxidative stress induced matrix metalloproteinase (NIMP) activation, collagen degradation and remodeling in pressure overload heart failure. We hypothesize that pressure overload leads to redox imbalance causing increased expression/activity of MMP-2/9 producing collagen degradation and heart failure. To test this hypothesis, we created pressure overload heart failure by abdominal aortic stenosis (AS) in wild-type C57BL/6J and collagen mutant (Collal with 129 s background) mice. At 4 weeks, post surgery, functional parameters were measured. Left ventricle (IV) tissue sections were analyzed by histology, Western Blot and PCR. The results suggest an increase in NOS with a decrease in eNOS, an increase in nitrated protein modification and depletion of antioxidants thioredoxin and SOD in pressure overload. MMP-2/9 expression/ activity and collagen degradation were increased in the AS animals. To determine whether a mutation in the collagen gene at the site of MMP cleavage mitigates cardiac hypertrophy, we used Collal mice. In these mice, the AS induced LV hypertrophy (LVH) was ameliorated. In conclusion, our results suggest that AS leads to increased oxidative stress, expression/activity of MMP-2/9 and a decrease in antioxidant expression producing collagen degradation and heart failure. European Society of Cardiology. Published by Elsevier B.V.