Background
We recently found that, right heart failure is largely driven by mitochondrial oxidative stress (mitoROS). In this study, we aim to examine interventricular differences with particular attention to mitochondrial function by using a genetic mouse model overexpressing human catalase in mitochondria.
Methods and Results
To evaluate interventricular differences under resting and increased-workload conditions, we characterized mitochondrial function by measuring oxygen consumption with an Oroboros O2k respirometer in isolated adult murine cardiomyocytes with (working) or without (baseline) prior electrical pacing. At baseline, RV cardiomyocytes showed significantly reduced mitochondrial complex activities, decreased leak respiration and electron transport chain capacity compared to LV cardiomyocytes (N=19). In line with the increased respiratory activity of baseline LV cardiomyocytes, oxidative stress was higher in LV than in RV cardiomyocytes as shown by significantly increased levels of hyperoxidized peroxiredoxin (p=0.006). In contrast, only working RV cardiomyocytes of Langendorff-perfused murine hearts with 30 min of electrical pacing (7 Hz) to induce increased workload, and upon pacing and additional complex III inhibition by antimycin to further increase mitoROS release, showed significantly increased oxidative stress levels and not LV cardiomyocytes (p=0.038; N=6). The higher levels of mitoROS in working RV cardiomyocytes might be related to a less efficient antioxidant defense system in RV compared to LV, as confirmed by significantly decreased expression of the mitochondrial superoxide dismutase (SOD2) in pressure-overloaded RV myocardium compared to pressure-overloaded LV myocardium (p=0.040). In accordance, the mitochondrial oxygen consumption rate was significantly lower in H2O2-pretreated (10 µM, 30 min) RV cardiomyocytes compared to LV cardiomyocytes, which might be due to oxidative modifications of respiratory chain complexes.
To translate these findings to an in-vivo model, we investigated mice overexpressing human mitochondrial catalase (mCAT) and wild-type littermates (WT) upon RV pressure overload induced by constricting the pulmonary artery (PAB) (N=17). Indeed, RV systolic function (TAPSE: WT PAB 0.70 ± 0.23 mCAT PAB 0.89 ± 0.17 p<0.008; Strain: WT PAB -7.1 ± 2.2 mCAT PAB -11.5 ± 2.8 p<0.0001), was significantly less impaired in mCAT compared to WT mice after 4 weeks of PAB. Exercise testing and molecular analysis of myocardial tissue from mice with cardiomyocyte-specific mCAT upon PAB will provide further mechanistic insight to the role of cardiomyocyte mitoROS in right heart failure.
Conclusion
Under pathophysiological conditions, the RV is more susceptible to oxidative damage than the LV which might be related to a lower antioxidant capacity and altered mitochondrial respiration. Consequently, protecting mitochondrial function by directly targeting mitoROS in RV pressure overload protects RV function and might be a promising therapeutic option to prevent RHF.
