Abstract 18260: Apolipoprotein A-I Mimetic Peptide, 4F Targets Lipoxygenases via miR193-3p Induction to Rescue Severe Pulmonary Hypertension

• DOI: 10.1161/circ.128.suppl_22.a18260
• Publication Date: 2024-04-23T10:56:54Z
• Authors: Salil Sharma; Gabe Wong; Soban Umar; David Meriwether; Mohamad Navab; Srinivasa T Reddy; Mansoureh Eghbali

Background: Pulmonary hypertension (PH) causes increase in pulmonary arterial pressure causing right ventricular (RV) hypertrophy and RV failure (RVF). We have shown that apolipoprotein A-I mimetic peptide 4F rescues advanced PH decreases circulating levels of oxidized fatty acids [hydroxyoctadecadienoic (HODEs) hydroxyeicosatetraenoic acids(HETEs)] the MCT rat-model PH. Here, we show rats mice by inducing miR-193-3p (miR193), which regulates enzymes responsible for production HETEs HODEs. Methods results: was induced monocrotaline (MCT, 60mg/kg,s.c. single injection) or hypoxia (O 2 ≤10%) 21 days. daily therapy intratracheal instillation miR193 were started after establishment both models (4F: 50mg/kg/day, s.c. from day 21-30 model 14-21 model; (20nM) at days 16, 26 14 18 model). (RVP) measured direct catheterization. Rats developed (RVP=67.12±1 vs. 29.8±1mmHg ctrl group) progressed to RVF 30 (RVP=74±1, p<0.05 vs ctrl). rescued (MCT model: RVP=46±3 mmHg, RVF; Hypoxia RVP=22±3.8 mmHg 36.91±5.74 20.93±2.52 normoxic mice). MicroRNA microarray qPCR showed a ~3 fold downregulation normalized treatment models. OE resulted ~2.5 gain lung tissue preexisting as RVPs significantly lower than group (38.2±5.5 MCT-rat ~25.3±0.97mmHg hypoxic-mice). MiR193 reversed increased arteriolar muscularization In vivo suppressed transcription lipooxygenases ALOX5, ALOX12 ALOX15. vitro human Arterial SMCs (hPASMC) with HODEs absence 4F. Lastly, decreased hPASMCs proliferation presence serum 12-HETE (100ng/ml) >2 folds (p<0.05 ctrl) whereas KD proliferation. Conclusion: severe targeting lipoxygenases.