Key result
Abdominal aortic stenosis in mice increased oxidative stress, MMP-2/9 expression, and collagen degradation, whereas a mutation in the collagen gene (Col1a1) ameliorated LV hypertrophy.
Why the study?
Does pressure overload induced by abdominal aortic stenosis cause oxidative stress, MMP-2/9 activation, and collagen degradation leading to heart failure in mice?
Does pressure overload induced by abdominal aortic stenosis cause oxidative stress, MMP-2/9 activation, and collagen degradation leading to heart failure in mice?
Pressure overload induces heart failure through oxidative stress-mediated MMP-2/9 activation and subsequent collagen degradation, a process ameliorated by mutating the MMP cleavage site on collagen.
No immediate change to HF care; leaves open whether MMP-2/9 inhibition prevents remodeling in patients.
Despite extensive strides in understanding pressure overload induced heart failure, there is very little known about oxidative stress induced matrix metalloproteinase (MMP) 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 (Col1a1 with 129 s background) mice. At 4 weeks, post surgery, functional parameters were measured. Left ventricle (LV) tissue sections were analyzed by histology, Western Blot and PCR. The results suggest an increase in iNOS 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 Col1a1 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.
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Henderson et al. (2007) studied Pressure overload induced chronic heart failure. Abdominal aortic stenosis (AS) vs. Wild-type vs Col1a1 mice was evaluated on LV hypertrophy, oxidative stress, and MMP-2/9 expression/activity. Abdominal aortic stenosis in mice increased oxidative stress, MMP-2/9 expression, and collagen degradation, whereas a mutation in the collagen gene (Col1a1) ameliorated LV hypertrophy.
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