Hypoxia-Induced miR-15a Promotes Mesenchymal Ablation and Adaptation to Hypoxia during Lung Development in Chicken

Abstract

The lungs undergo changes that are adaptive for high elevation in certain animal species. In chickens, animals bred at high elevations (e.g., Tibet chickens) are better able to hatch and survive under high-altitude conditions. In addition, lowland chicken breeds undergo physiological effects and suffer greater mortality when they are exposed to hypoxic conditions during embryonic development. Although these physiological effects have been noted, the mechanisms that are responsible for hypoxia-induced changes in lung development and function are not known. Here we have examined the role of a particular microRNA (miRNA) in the regulation of lung development under hypoxic conditions. When chicks were incubated in low oxygen (hypoxia), miR-15a was significantly increased in embryonic lung tissue. The expression level of miR-15a in hypoxic Tibet chicken embryos increased and remained relatively high at embryonic day (E)16–20, whereas in normal chickens, expression increased and peaked at E19–20, at which time the cross-current gas exchange system (CCGS) is developing. Bcl-2 was a translationally repressed target of miR-15a in these chickens. miR-16, a cluster and family member of miR-15a, was detected but did not participate in the posttranscriptional regulation of bcl-2. Around E19, the hypoxia-induced decrease in Bcl-2 protein resulted in apoptosis in the mesenchyme around the migrating tubes, which led to an expansion and migration of the tubes that would become the air capillary network and the CCGS. Thus, interfering with miR-15a expression in lung tissue may be a novel therapeutic strategy for hypoxia insults and altitude adaptation.

Oxygen tension modulates extracellular vesicles and its miRNA contents in bovine embryo culture medium

“…It is known that serotonin protects the placenta against cellular apoptosis (Hadden et al, ), whereas the miRNA‐15a, which was lower in EVs from high oxygen tension, has been reported as a regulator of serotonin transporter levels in human placenta (Moya, Wendland, Salemme, Fried, & Murphy, ). Similar to our results, another study demonstrated the increase of miR‐15a in low oxygen condition in chicken eggs (Hao, Hu, Wu, & Li, ). Thus, the presence of altered miRNAs in high oxygen tension on Day 3 of embryo development suggests disturbed regulation of important pathways associated with the success of embryonic development compared to miRNA profile in EVs isolated from media in low oxygen tension, which is close to physiological conditions.…”

Long non‑coding RNA SNHG16 inhibits the oxygen‑glucose deprivation and reoxygenation‑induced apoptosis in human brain microvascular endothelial cells by regulating miR‑15a‑5p/bcl‑2

“…Bcl-2 is a regulator of cell survival and apoptosis and a potential target of miR-15a-5p ( 24 ). Accordingly, it was hypothesized that SNHG16 inhibited OGD-R-induced apoptosis by antagonizing miR-15a-5p to upregulate Bcl-2 in hBMECs.…”

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

“…Previous reports have also demonstrated that the miR-15a/16-1 miRNA cluster functions as a tumor suppressor, targeting Bcl-2 protein in prostate tumor cells (21)(22)(23)32,33). Inhibition of cell proliferation by miR-15a/16-1 has been reported to occur in both lymphoid and nonlymphoid tissue (21-23,32,33,37,38), Wang et al (40) further demonstrated the miR15a level is increased and it induces cell death in an ischemia reperfusion model (39,41). Our current studies revealed a differential effect of miR-15a/16 on apoptosis in nontumor lung epithelial cells.…”