Abstract 31: Functional Impact of Inflammatory Cell-Originating HDL-miR-223 Communication in vivo
Atherosclerosis is associated with endothelial dysfunction and inflammation, and high-density lipoproteins (HDL) play critical roles in both. HDL transport a wide-variety of proteins, nucleic acids, and small molecules, which likely confer many of HDL’s alternative functions, including its anti-inflammatory and anti-atherogenic properties. Using in vitro studies, we demonstrated that macrophages export miR-223 to HDL and subsequently, HDL delivers functional miR-223 to human coronary artery endothelial cells (HCAEC). Moreover, intracellular adhesion molecule 1 (ICAM-1), a miR-223 target, was found to be down-regulated by HDL-miR-223 at a specific target site within ICAM-1’s 3’ untranslated region. These in vitro findings support the potential of a HDL-miRNA communication pathway that may contribute to atherogenesis. To validate HDL-miRNA communication in vivo, bone-marrow transplant (BMT) studies were completed with Mir223-/- and C57B/6J (WT) mice. To demonstrate that functional HDL-miR-223 is delivered to recipient cells/tissues in vivo, BM from WT mice was transplanted into irradiated Mir223-/- mice. Strikingly, we found that HDL-miR-223 communication was restored after BMT, as evidenced by significantly increased miR-223 levels on HDL and in the liver, white adipose, aortic endothelium, and skeletal muscle. Conversely, HDL-miR-223 intercellular communication was depleted by transplanting BM from Mir223-/- into WT mice, and resulted in significant loss of miR-223 on HDL and in many tissues. In both BMT studies, miR-223 changes led to altered expression of many target genes in multiple tissues. Most importantly, these studies identified a novel miR-223 target gene which we experimentally validated, vesicle transport through interaction with t-SNAREs homolog 1A (VTI1A), which was decreased and increased in the aortic endothelium from each BMT study, respectively. VTI1A has been previously characterized as a SNARE protein that contributes to cytokine secretion and membrane lipid dynamics. As such, HDL likely mediates an inflammatory cell-originating miR-223 communication pathway that suppresses inflammation and cytokine secretion in the aortic endothelium, thus antagonizing atherosclerosis.
Author Disclosures: C.B. Wiese: None. L.A. Roteta: None. W. Zhu: None. S.R. Landstreet: None. K.C. Vickers: None.
- © 2015 by American Heart Association, Inc.