Pressure Overload Instigates Remodeling in Ailing to Failing Myocardium in Mice

Abstract

The increase in the levels of nitrotyrosine and activation of MMP (matrix metalloproteinase)-2/9 play an important role in ailing to failing myocardium. The hypothesis is that an increase in pressure within the heart leads to the increased formation of reactive oxygen species (ROS) which generates nitrotyrosine that induces MMP-2/9 activation. To test this hypothesis, pressure overload was created in C57BL/6J mice by occluding the abdominal aorta above the left kidney (aortic stenosis-AS) and the sham without the occlusion. The results suggested an increase in LVEDd from 2.83 ± 0.07 in control to 3.81 ± 0.13 (p < 0.05) in AS mice. Fractional shortening was decreased from 39.85 ± 0.85 in control to 27.55 ± 1.04 (p < 0.05) in AS mice. The ECG waves had a shorter R-R interval with lower amplitudes in the AS animals in comparison to control suggesting tachycardia. Histological data revealed increased LV hypertrophy and structural changes in the AS animals as compared to control. Also the AS animals had larger lung weight, suggesting edema due to the increase in pressure, and a smaller renal mass, suggesting ischemia to the kidney. Zymography analysis revealed an increase in MMP-2/9 activity in the AS heart. Western Blot analysis showed a decrease in TIMP-1/4, (tissue inhibitors of matrix metalloproteinase) and increased collagen fragments and nitrotyrosine in AS animals. PCR data was marked by increases in MMP-2/9 (figure) and NADPH oxidase activity with a decrease in thiroredoxin and peroxiredoxin in the AS heart over four weeks. Figure 1Open in figure viewerPowerPoint These data support the hypothesis that pressure overload causes an increase in nitrotyrosine and ROS which lead to the activation of MMP-2/9 causing overt heart failure.