Abstract 14798: Cellular Release and Uptake of MicroRNA-210 Regulates Hypoxic Adaptation in Recipient Vascular Tissue
Background: Hypoxia induces adaptive and pathogenic cellular responses, many of which are controlled by microRNA (miRNA). Plasma-based extracellular miRNA have been measured in ischemic and hypoxia-dependent cardiovascular diseases; yet, their regulation and in vivo biological functions remain enigmatic.
Objective: Determine the role of the hypoxia-inducible miR-210 as a circulating messenger controlling hypoxic adaptation in recipient vascular tissue.
Results: MiR-210 is released from hypoxic (4.8 fold-change+ 0.2 SEM) and re-oxygenated (7.5 fold change+0.3) vascular endothelial cells in culture. Plasma levels of miR-210 are elevated in mice chronically exposed to hypoxia (2.1 fold-change+0.4, N=6 mice/group). MiR-210 is also up-regulated in plasma from humans subjected chronically to high altitude (3.7 fold-change+0.7, N=5 Andean women/group at week 36 pregnancy residing at high and low altitudes) and from PAD patients with intermittent claudication (3.5 fold-change+0.7 vs. healthy control, N=16/group). Size-exclusion chromatography reveals that extracellular miR-210 is not associated with 30-100 nm microvesicles (exosomes). Rather, it co-immunoprecipitates with the RNA binding protein AGO2 in >100 kDa complexes. Extracellular miR-210 can be delivered to cultured vascular smooth muscle cells (2.7 fold-change+0.2) and to miR-210-genetically null fibroblasts (263 fold-change+11 above the level of detection), thus confirming direct miRNA uptake. Delivered miR-210 only appears active in hypoxia, as revealed by repression of both a reporter gene carrying a miR-210-specific target site and its endogenous target ISCU1/2. Down-regulation of ISCU1/2 reduces mitochondrial respiratory Complex I activity (0.7 fold-change+0.02) and is consistent with the known adaptive metabolic functions of miR-210. Finally, preliminary studies demonstrate that injection of miR-210-null mice with serum endogenously enriched for miR-210 increases intracellular levels of miR-210 in a variety of tissues (i.e., 1.8 fold-change+0.3 in liver; 5.5 fold-change+0.9 in aorta, N=3 mice/group).
Conclusions: Extracellular miR-210 is released in circulating plasma in vivo and can be delivered to recipient tissue to regulate hypoxic adaptation.
- © 2012 by American Heart Association, Inc.