The ability of the right ventricle (RV) to compensate pressure overload is determining survival in pulmonary arterial hypertension (PAH). Nitric oxide (NO) reduces the RV afterload through pulmonary vasodilation, but excessive NO amounts cause oxidative stress. Oxidative stress drives remodeling of pulmonary arteries and the RV. Here, we hypothesized that NO synthase 2 (NOS2) induction leads to excessive NO amounts that contribute to oxidative stress and impairs RV adaption to PAH. We utilized a surgical pulmonary artery banding (PAB) mouse model where RV dysfunction and remodeling occur independent from changes in the pulmonary vasculature. Three weeks after PAB, NOS2 expression was increased 2-fold in the hypertrophied RV on transcript and protein level together with increased NO production. Histomorphology localized NOS2 in interstitial and perivascular cardiac fibroblasts (CFs) after PAB, confirmed by cell isolation experiments. In the hypertrophied RV, NOS2 induction was accompanied by an increased formation of reactive oxidants - blocked by ex vivo NOS inhibition. We show that reactive oxidant formation in the hypertrophied RV is in part NOS2-dependent (in NOS2-deficient mice (NOS2-/-)). Lack of NOS2 induction prevented superoxide scavenging and decreased reactive oxidant formation. Functional measures of cardiac function by non-invasive echocardiography along with intra-cardiac catheterization revealed no differences in heart function between both genotypes after PAB. However, reduced NO and reactive oxidant formation in the hypertrophied RV of NOS2-/- mice was linked to reduced collagen accumulation through reduced collagen deposition from the cardiac fibroblast. Together, our data demonstrate a pro-fibrotic role for NOS2 induction in the hypertrophied RV.
- Boehm, M.
- Novoyatleva, T.
- Kojonazarov, B.
- Veit, F.
- Weissmann, N.
- Ghofrani, H. A.
- Seeger, W.
- Schermuly, R. T.
Keywords
- Cardiac Fibrosis
- Nitric Oxide Synthase
- Pulmonary Hypertension
- Right ventricle
