Function of NADPH oxidase 1 in pulmonary arterial smooth muscle cells from monocrotaline-induced pulmonary hypertension

Chronic alveolar hypoxia induces pulmonary hypertension (PH) and pulmonary vascular remodeling. Reactive oxygen species (ROS) are thought to play a major role in this process. Recent findings suggested that ROS production by NADPH oxidase 4 (Nox4) is plays an important role for PH development in hypoxia-induced PH in mice and human idiopathic pulmonary arterial hypertension (IPAH). Against this background we investigated whether NADPH oxidases are also active in PH development induced by monocrotaline (MCT) in rats. ROS production, their possible sources and their impact on the function of pulmonary arterial smooth muscle cells (PASMC) was observed.

MCT-PASMC showed an increased intracellular superoxide production, migration and proliferation as compared to healthy controls due to increased Nox1 expression. Comparing PASMC from MCT-treated and non-treated rats revealed an upregulation of Sod2, Nrf2 and cyclin D1, as well as an increased phosphorylation of cofilin. However, only Nrf2 and cyclin D1 turned out to be Nox1 dependent.

In conclusion, we showed that in contrast to hypoxia-induced PH not Nox4 but Nox1 is a key regulator of proliferation and migration in PASMC. Our data provided evidence that an upregulation of superoxide derived from increased Nox1 expression enhances proliferation and migration of PASMC. Proliferation is most probably increased via cyclin D1. Thus, different Nox isoforms maybe contribute to PH development in in PH of different origin.