Impact of S-Adenosylmethionine Decarboxylase 1 in Pulmonary Vascular Remodeling
Background—Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here we aimed to investigate whether 1) chronic hypoxia-induced PH in mice can be reversed by reoxygenation and 2) possible regression can be used to identify pathways activated during reversal and development of PH by genome-wide screening.
Methods and Results—Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most down regulated genes. In-situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased proliferation of pulmonary arterial smooth muscle cells and diminished PLC-γ1 phosphorylation. Compared to respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by Egr1 as a consequence of EGF stimulation. Key findings from the animal model were confirmed in human IPAH.
Conclusions—Our study indicates that genome-wide screening in mice from a PH model where full reversal of PH occurs, can be useful to identify potential key candidates for reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy.
- Received September 24, 2013.
- Revision received January 8, 2014.
- Accepted January 9, 2014.