Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w |
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Differential effects of the antioxidative agent nitro-oleic acid on the right and left ventricle in a mouse model of heart failure with preserved ejection fraction | ||
C. Bischof1, T. Schubert1, M. Müller1, U. Schlomann1, L. Lengenfelder1, V. Rudolph2, A. Klinke1 | ||
1Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 2Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; | ||
Background: Pulmonary
hypertension (PH) due to left heart disease is the most common PH group with an
about 20-50% prevalence of right ventricular (RV) dysfunction in patients with heart
failure with preserved ejection fraction (HFpEF), where RV dysfunction (RVD) is
associated with poor clinical outcome. The pathophysiology of HFpEF is
multifactorial and treatment options are insufficient. Recently, we found that
antioxidative effects in the left ventricular (LV) myocardium related to
treatment with nitro-oleic acid (NO2-OA) contributed to the
amelioration of LV diastolic function in a HFpEF mouse model. Recently, we
could identify mitochondrial oxidative stress to be importantly involved in
progression of RVD upon pulmonary artery banding. Here, we aim to investigate
RVD and potential treatment options in murine HFpEF.
Methods and Results: HFpEF was induced by a combination of high fat diet (HFD) and endothelial NO synthase (eNOS) inhibition with L-NAME for 15 weeks in C57BL/6N mice. At week 11, mice received either NO2-OA or vehicle via mini-osmotic pumps for 4 weeks. As previously reported, treatment with NO2-OA significantly improved LV diastolic function. Echocardiographic analysis of RV function now revealed, that tricuspid annular plane systolic excursion (TAPSE) in the HFpEF mouse model at 15 weeks was significantly decreased compared to mice receiving normal chow (TAPSE, mean ± SD; chow: 1.17 ± 0.13; HFD+L-NAME: 0.91 ± 018; N=10, p<0.01). Whereas treatment with NO2-OA significantly alleviated diastolic LV dysfunction, RV function was not changed by NO2-OA administration (TAPSE, mean ± SD; HFD+L-NAME: 0.91 ± 018; HFD+L-NAME NO2-OA: 0.97 ± 0.20; N=10/11, p>0.99). While we on the one hand cannot rule out that RV dysfunction might be diminished after longer time periods of treatment at the moment, it might on the other hand point towards intraventricular differences in the underlying pathomechanisms. To unravel these potential differences, we analysed superoxide dismutases (SOD) as important mediators of redox regulation and markers of oxidative stress in RV and LV, given that NO2-OA is known to have antioxidative properties. In HFpEF vehicle-treated mice, mRNA expression of the SOD isoform 1, which is mainly expressed in the cytoplasm, was significantly upregulated in the LV (p<0.01), but not in RV tissue compared to mice fed with normal chow. In contrast, SOD2, an isoform exclusively located to mitochondria, was significantly upregulated in RV (p<0.05) but not in LV tissue. Interestingly, treatment with NO2-OA blunted the SOD1 upregulation in the LV, but had no effect on SOD2 expression in RV tissue. Differences in redox regulation in RV and LV myocardium were also disclosed in experiments with Langendorff-perfused mouse hearts with hydrogen peroxide. In RV myocardium the extent of hyperoxidized peroxiredoxin, a marker of oxidative stress, was higher compared to LV myocardium. Conclusion: RV dysfunction, an important determinant of mortality in HFpEF patients, was observed in a mouse model of HFpEF induced by a combination of HFD and eNOS inhibition. Treatment with NO2-OA, a cardioprotective and antioxidative agent, ameliorated LV diastolic function, but could not target RV dysfunction, which might be related to differential regulations of oxidative stress. Antioxidative strategies directly targeting mitochondrial integrity might by a promising approach to prevent RV dysfunction in HFpEF. |
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https://dgk.org/kongress_programme/jt2023/aP2251.html |