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MiR-212-5p Is a Potential Therapeutic Tool in Treatment of Pulmonary Hypertension

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A4616 - MiR-212-5p Is a Potential Therapeutic Tool in Treatment of Pulmonary Hypertension
Author Block: T. Chen, M. Sun, R. Ramchandran, Q. Zhou, J. Raj; Pediatrics, UIC, Chicago, IL, United States.
Rationale: We have found that pulmonary arterial endothelial cell (PAEC) release microvesicles (MV) both under normoxia (N) and hypoxia (H) and that hypoxic MV (H-MV) can induce pulmonary arterial smooth muscle cell (PASMC) proliferation in-vitro and pulmonary hypertension (PH) in mice in-vivo. We also found that hypoxia altered the expression of miRNA in the MV. Among the identified miRNAs, miR-212-5p expression was increased in H-MV and it showed the strongest anti-proliferative effect on PASMC. In this study, we sought to investigate the potential role of miR-212-5p in amelioration of PH utilizing the hypoxia-induced PH mouse model. Methods: We exposed mouse PAEC and PASMC to normoxia or hypoxia (1% O2) in-vitro and measured miR-212-5p level in the cells by qRT-PCR. We also isolated PASMC from mice exposed to normoxia or hypoxia (10% O2) for 3 weeks and measured miR-212-5p in the isolated PASMC by qRT-PCR. Next, we injected 8-week old C57BL/6J wildtype mice with miR-212-5p mimics or inhibitors (Ambion) through the tail vein, twice a week for 3 weeks, during normoxia or hypoxia (10% O2). Then we measured right ventricular systolic pressure (RVSP), RV hypertrophy [RV/(LV+S) ratio], and pulmonary arterial wall thickness in these mice. Negative control miRNA mimics or Negative control miRNA inhibitors (Ambion) served as controls for the experiments with mimic or inhibitors, respectively. Results: We found that hypoxia induced miR-212-5p expression in PAEC, but not in PASMC, in-vitro. However, hypoxia induced the expression of miR-212-5p in PASMC in-vivo, suggesting that the increase in miR-212-5p expression in PASMC may require the presence of other cells, specifically endothelial cells. We also found that injection of miR-212-5p mimics suppressed the hypoxia-induced increase in RVSP and pulmonary vessel wall remodeling in mice, indicating that miR-212-5p attenuates hypoxia-induced PH. Inhibition of miR-212-5p with antagomirs further increased the hypoxia-induced increase in RVSP and RV hypertrophy, indicating that miR-212-5p plays a protective role in hypoxia-induced PH in mice. Conclusions: Our results suggest that in-vivo miR-212-5p is induced as an adaptive response to hypoxia, and acts as a “brake” to suppress PH progression. We suggest that miR-212-5p may be a potential therapeutic tool in the treatment of PH.
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