Mechanisms that decrease human Neprilysin gene expression in cigarette smoke‐induced pulmonary vascular disease

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We previously demonstrated that lung neprilysin (NEP) may be protective against cigarette smoke (CS)‐induced pulmonary vascular remodeling, a major contributor to pulmonary hypertension (PHTN) in lung disorders/diseases, such as chronic obstructive pulmonary disease (COPD). We found decreased NEP levels in COPD lung, at least some of which are due to changes in NEP transcription that may involve epigenetic mechanisms, but not ROS‐induced NEP gene damage or NEP gene promoter methylation. The goal of the present study is to identify CS‐induced mechanisms that decrease NEP gene transcription. We now present evidence that histone proteins may be modified (methylated, deacetylated) and decrease NEP transcription in response to CS. This is shown with human PA SMCs in ChIP experiments with antibodies to modified histone proteins (H3ac, H3K9me2), and with the compounds 5‐Aza‐2′deoxycytidine, Trichostatin A, or Valproic Acid. CS‐specific changes in regulatory or transcription factor (HIF‐1 and 2, NFkB) binding to the NEP gene that could decrease NEP transcription are also investigated in ChIP experiments with PA SMCs. Our results may suggest new ways to increase endogenous pulmonary NEP levels to treat or prevent smoke or hypoxia‐induced pulmonary vascular remodeling.Support: NHLBI RO3‐HL‐095430, NHLBI PPG P05 HL014985 and VA Merit.