Background:

Right ventricular (RV) dysfunction is associated with poor clinical outcomes independently of the underlying disease. In today’s clinical routine, no therapeutic options are available that specifically target right heart failure. Accumulating evidence points towards inflammation and oxidative stress as well as a dysregulation of substrate metabolism to be involved in the pathogenesis of RV dysfunction. Nitro-fatty acids like nitro-oleic acid (NO₂-OA) have recently been identified as potent anti-oxidative and anti-inflammatory molecules that have been proven to alleviate cardiac remodelling in different mouse models.

We aimed to test whether application of NO₂-OA modulates RV remodelling and function in a mouse model of RV pressure overload induced by pulmonary artery banding (PAB).

Methods and Results:

Pulmonary artery banding was induced in C57bl/6J wild type mice by constricting the pulmonary artery to a diameter of 300 µm. Mice continuously received either NO₂-OA or vehicle via osmotic minipumps implanted immediately after PAB. After 4 weeks of treatment, RV morphology and function were assessed by echocardiography. RV tissue was harvested and expression analyses of enzymes involved in substrate metabolism was performed.

RV function reflected by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE) were significantly impaired after PAB and were improved by treatment with NO₂-OA compared to vehicle in pressure-overloaded ventricles (PAB NO₂-OA vs. PAB vehicle, mean ± SEM, FAC: 22 ± 1.9% vs. 14 ± 1.5%, p=0.0028; TAPSE: 0.96 ± 0.042 mm vs. 0.8 ± 0.036 mm, p=0.03; N=9,15). RV dilatation reflected by inner diameter was less pronounced in NO₂-OA-treated animals compared to vehicle (PAB NO₂-OA vs. PAB vehicle 2.1 ± 0.1 mm vs. 2.5 ± 0.09 mm, p=0.04, N=9, 15). An increase of RV wall thickness was attenuated by NO₂-OA (PAB NO₂-OA vs. PAB vehicle 0.53 ± 0.039 mm vs. 0.7 ± 0.039 mm, p=0.0029, N=9, 15), indicating that NO₂-OA diminished hypertrophic remodelling. The mRNA expression of the enzymes, pyruvate dehydrogenase kinase 1 (PDK1) and citrate synthase (CS), both importantly involved in substrate metabolism in cardiomyocytes and known to be dysregulated during progression of heart failure, was profoundly altered in vehicle-treated PAB animals compared to controls, which was less evident in NO₂-OA-treated PAB mice (PAB vs. ctrl, PDK1: 1.29 ± 0.11 vs. 0.97 ± 0.09 , p=0.13; CS: 0.92 ± 0.07 vs. 1.32 ± 0.15, p=0.17; PAB NO₂-OA vs. PAB vehicle, PDK1: 0.81 ± 0.09 vs. 1.29 ± 0.11, p=0.008; CS: 1.15 ± 0.08 vs. 0.92 ± 0.07, p=0.055; N=5,11).

Conclusion:

RV pressure overload provokes RV hypertrophy and dysfunction, which can be alleviated by application of NO₂-OA. Further experiments will expand these findings to validate the characterization of RV function and to identify underlying molecular mechanisms.