The mitochondria-targeted antioxidant mitoTEMPO has protective effects in mouse models of right ventricular pressure overload

Elfi Donhauser (Bad Oeynhausen)1, T. Kapries (Bad Oeynhausen)1, A. Seidinger (Bochum)2, A. Ridder (Bochum)2, M. Müller (Bad Oeynhausen)1, C. Welke (Bad Oeynhausen)1, D. Wenzel (Bochum)2, V. Rudolph (Bad Oeynhausen)3, A. Klinke (Bad Oeynhausen)3

1Herz- und Diabeteszentrum NRW Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung Bad Oeynhausen, Deutschland; 2Ruhr-Universität Bochum Abteilung für Systemphysiologie Bochum, Deutschland; 3Herz- und Diabeteszentrum NRW Allgemeine und Interventionelle Kardiologie/Angiologie Bad Oeynhausen, Deutschland


Background: Right heart failure (RHF) is a late sequela of many cardiovascular disease processes and a driver of mortality. To advance the development of therapies targeting the right ventricle (RV), it is essential to understand pathomechanisms of the disease. We have recently identified mitochondrial oxidative stress in cardiomyocytes to contribute to the development of RHF. Therefore, we sought to test the therapeutic potential of the mitochondria-targeted antioxidant mitoTEMPO in mouse models of RV pressure overload.

Methods and Results: To investigate the therapeutic potential of the mitochondria-targeted antioxidant mitoTEMPO in RV pressure overload, we employed the two mouse models of pulmonary artery banding (PAB) and pulmonary hypertension (PH) induced by Sugen 5416 and chronic hypoxia (SuHx) using C57BL/6N mice. PAB was induced by constricting the pulmonary artery (PA) to a diameter of 300 µm for a period of 6 weeks. Sugen 5416 was administered once weekly during exposure of mice to normobaric hypoxia (10% oxygen) for 3 weeks. Mice were treated with mitoTEMPO (0.7 mg/kg/day) for the total time periods via osmotic minipumps. After 6 weeks of PAB, echocardiography was performed to assess RV function. In SuHx mice RV systolic pressure (RVSP) was determined by right heart catheterisation after 3 weeks. In PAB, mitoTEMPO application significantly improved systolic RV function, reflected by tricuspid annular plane systolic excursion (TAPSE) (untreated 0.5 mm ± 0.1 mm vs. mitoTEMPO 0.7 mm ± 0.1 mm; mean ± SD; p<0.05). However, RV hypertrophy and right atrial and RV dilation was not reduced. In contrast to these mild improvements of RV function, the presence and severity of RHF reflected by the extent of hepatic venous congestion, ascites, restricted mobility and increased breathing were profoundly ameliorated by mitoTEMPO treatment after 6 weeks in PAB mice (p<0.0001). On the contrary to the absent effect of mitoTEMPO on RV hypertrophy in PAB mice, in SuHx mice RVSP, RV weight related to tibia length and Fulton index were significantly decreased after 3 weeks of mitoTEMPO treatment compared to non-treated mice (RVSP: untreated 34.6 mmHg ± 3.4 mmHg vs. mitoTEMPO 30.8 mmHg ± 2.4 mmHg, p<0.05; RV/tibia: untreated 0.49 mg/mm ± 0.03 mg/mm vs. mitoTEMPO 0.36 mg/mm ± 0.05 mg/mm, p<0.0001; Fulton index: untreated 0.38 ± 0.04 vs. mitoTEMPO: 0.32 ± 0.06, p<0.05; mean ± SD). Histological analysis of pulmonary arterioles of these mice will disclose whether mitoTEMPO reduced adverse vascular structural remodeling.

Conclusion: Treatment of mice exposed to RV pressure overload with mitoTEMPO had a protective impact. Further analyses will help to understand, whether mitoTEMPO-dependent reduction of oxidative stress can directly affect RV function, or whether improvements are rather derived from vascular effects. These data may help to better characterise the potential of mitochondria-targeted antioxidants for the treatment of RHF.
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