Aims and Background

In rats decreased NO bioavailability induces right heart failure but compensatory hypertrophy in the left ventricle. Thus, both ventricles respond to the same stressor in a different way. An inability of the right ventricle to antagonize oxidative stress caused by NO deficiency may contribute to this different responsiveness. Oxidative stress leads to an activation of matrix metalloproteinase-2 (MMP2). MMP2, however, can contribute to heart failure. Therefore, we addressed the question whether increasing oxidative defense by administration of the SOD mimetic Tempol or direct inhibition of MMP2 activity by SB-3CT mitigates right heart failure under these conditions.

 

Material and Methods

Rats received L-NAME for 4 weeks via tap water. During week three and four treatment groups received either Tempol or SB-3CT in addition to L-NAME. After four weeks left and right heart function was analyzed by echocardiography and subsequently all rats were sacrificed for organ preparation. Organ weights and mRNA expression of NPPB and Col1A1 were analyzed. MMP2 activity was quantified by proteolytic auto-activation, zymography, and troponin I degradation.

 

Results

Neither Tempol nor SB-3CT affected L-NAME-induced hypertension. However, whereas Tempol and SB-3CT did not affect left ventricular weight they mitigated right ventricular hypertrophy. On the molecular level, SB-3CT attenuated the expression of cardiac-specific genes in the right ventricle, such as NPPB, whereas Tempol preferentially affected the expression of fibrotic genes (i.e. Col1A1). L-NAME induced MMP2 activity in the right ventricle was much stronger than in left ventricle, and therefore induced the degradation of troponin I, a MMP2 substrate, in right but not left ventricles. Furthermore, L-NAME reduced right ventricular function as indicated by strongly reduced RV % Area Change and TAPSE, but SB-3CT and Tempol slightly improved these parameters.

 

Conclusion

MMP2 activity and oxidative stress contribute both to the selective right ventricular failure in this model of hypertension. Oxidative stress seems to be linked more specific to events linked to cardiac fibrosis whereas MMP2 preferentially affects cardiomyocytes-specific targets as shown for troponin I. In conclusion, the right ventricle is more sensitive to reduction in NO bioavailability than the left ventricle.