Nitric Oxide Synthase 2 Induction Promotes Right Ventricular Fibrosis.

Abstract

The ability of the right ventricle to compensate pressure overload determines survival in pulmonary arterial hypertension (PAH). Nitric oxide (NO) reduces the right ventricular afterload through pulmonary vasodilation, but excessive NO amounts cause oxidative stress. Oxidative stress drives remodeling of pulmonary arteries and the right ventricle. In the present study, we hypothesized that nitric oxide synthase 2 (NOS2) induction leads to excessive NO amounts that contribute to oxidative stress and impair right ventricular adaptation to PAH. We used a surgical pulmonary artery banding (PAB) mouse model in which right ventricular dysfunction and remodeling occur independently of changes in the pulmonary vasculature. Three weeks after PAB, NOS2 expression was increased twofold in the hypertrophied right ventricle on transcript and protein levels together with increased NO production. Histomorphology localized NOS2 in interstitial and perivascular cardiac fibroblasts after PAB, which was confirmed by cell isolation experiments. In the hypertrophied right ventricle, 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 right ventricle 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 noninvasive echocardiography together with intracardiac catheterization revealed no differences in heart function between both genotypes after PAB. However, reduced NO and reactive oxidant formation in the hypertrophied right ventricle of NOS2-/- mice was linked to reduced collagen accumulation through reduced collagen deposition from the cardiac fibroblast. Together, our data demonstrate a profibrotic role for NOS2 induction in the hypertrophied right ventricle.

• Authors: Mario Boehm, Tatyana Novoyatleva, Baktybek Kojonazarov, Florian Veit, Norbert Weissmann, Hossein A Ghofrani, Werner Seeger, Ralph T Schermuly
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 60 Issue 3 Pg. 346-356 (03 2019) ISSN: 1535-4989 [Electronic] United States
• PMID: 30277804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• Disease Models, Animal
• Fibrosis (metabolism)
• Heart Ventricles (metabolism)
• Hypertension, Pulmonary (metabolism)
• Hypertrophy, Right Ventricular (metabolism)
• Male
• Mice, Inbred C57BL
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Oxidative Stress (physiology)
• Pulmonary Artery (metabolism)
• Ventricular Dysfunction, Right (metabolism)
• Ventricular Function, Right (physiology)
• Ventricular Remodeling (physiology)