AAV (Serotype 5)

Activation of pulmonary epicardial fibroblasts is a key factor in pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies have shown that miRNA is involved in the regulation of fibroblast activation. Here, researchers found that hypoxia-induced activation of lung epicardial fibroblasts was accompanied by a sharp decrease in miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1α or Smad3 reversed the hypoxia-induced decrease in miR-29-3p in cultured lung adventitial fibroblasts. In in vitro experiments, miR-29a-3p mimics can inhibit the proliferation, migration, and secretion of hypoxia-induced pulmonary adventitial fibroblasts, and suppress the hypoxia-induced expression of α-smooth muscle actin and extracellular matrix collagen in pulmonary adventitial fibroblasts. However, the miR-29a-3p inhibitor can simulate the effect of hypoxia on the activation of pulmonary adventitial fibroblasts. Further studies found that preventive or therapeutic use of miR-29a-3p can significantly reduce pulmonary artery pressure and right ventricular hypertrophy index and improve pulmonary vascular remodeling in rats with hypoxic pulmonary hypertension. These results suggest that miR-29a-3p regulates the activation and phenotype of pulmonary epicardial fibroblasts under hypoxic conditions and has preventative and therapeutic potential in hypoxic pulmonary hypertension.

To evaluate the therapeutic effect of miR-29a on hypoxic pulmonary hypertension (HPH), rats were injected with adeno-associated virus (AAV)5-miR-29a and AAV5 control vector after 4 weeks of hypoxia and then placed in hypoxia for an additional 2 weeks. AAV5-miR-29a significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) (Figure 1A and 1B). Hypoxia significantly increased MT% and MA% in pulmonary arteries, respectively, whereas AAV5-miR-29a treatment significantly reduced the hypoxia-induced increases in MT% and MA% (Figure 1C-1E). However, prophylactic or therapeutic administration of AAV5 controls had no such effect (Figure 1A-1E). Prophylactic or therapeutic administration of AAV5-miR29a had no significant effect on mean carotid pressure. In addition, the researchers measured the expression of miR-29a-3p in the pulmonary adventitia isolated from the rats administrated with AAV5-miR-29a or AAV5-control. Hypoxia significantly reduced the expression of miR-29a-3p in the lung adventitia by more than 31-fold (Figure 1F). These results indicate that miR-29a-3p has preventive and therapeutic effects on HPH in rats.

Figure 1. Therapeutic effects of miR-29a on hypoxic pulmonary hypertension (HPH) in rats. (Luo Y, et al., 2015)