ApoA-I Mimetic Peptide 4F Rescues Pulmonary Hypertension by Inducing MicroRNA-193-3p
Background—Pulmonary Arterial Hypertension (PAH) is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) is well established in vascular disease. Apolipoprotein A-I (apoA-I) mimetic peptides including 4F have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of PAH and the therapeutic action of 4F in PAH is not well established.
Methods and Results—We studied two different rodent models of Pulmonary Hypertension (PH); a monocrotaline (MCT) rat model and a hypoxia mouse model. Plasma levels of HETEs and HODEs were significantly elevated in PH. 4F treatment reduced these levels and rescued pre-existing PH in both models. MicroRNA analysis revealed that miR193-3p (miR193) was significantly downregulated in the lung tissue and in serum from both PAH patients and in PH rodents. In-vivo miR193 overexpression in the lungs rescued pre-existing PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor alpha (RXRα).
Conclusions—These studies establish the importance of microRNAs as downstream effectors of an apoA-I mimetic peptide in the rescue of PH and suggest that treatment with apoA-I mimetic peptides, or miR193 may have therapeutic value.
- Received March 31, 2014.
- Revision received June 2, 2014.
- Accepted June 16, 2014.