Abstract 18542: Genetic Ablation of miR-33 Attenuates Inflammation and Reduces Abdominal Aortic Aneurysm Formation
Introduction: Abdominal aortic aneurysm (AAA) pathogenesis is characterized by inflammation and matrix degradation, part of which are observed in atherosclerosis. Despite statins are only clinically effective agents for AAA, their effects are limited and more effective therapies are expected. Previous studies suggested that microRNA(miR)-33 inhibition and genetic ablation of miR-33 increase serum HDL cholesterol (HDL-C) and attenuates atherosclerosis. Although several miRs are reported to affect AAA, such miRs which target cholesterol metabolism have not been reported ever.
Hypothesis: MiR-33 may be involved in AAA pathogenesis, and anti-miR-33 can be an effective therapy.
Methods: We assessed the phenotypic difference of CaCl2-induced and Angiotensin(AT)II-induced AAA models between miR-33+/+ and miR-33-/- mice. To elucidate the underling mechanisms, we assessed the functions of macrophages (MΦ), primary aortic vascular smooth muscle cells (VSMCs) and HDL-C between these mice.
Results: CaCl2-induced AAA model in miR-33-/- mice revealed that miR-33 deficiency resulted in a decline of AAA development. When crossed with Apoe-/- mice and infused with AT II for 4 weeks, miR-33-/-Apoe-/-mice showed decreased aortic diameter compared with control mice. Reduced accumulation of MΦ and MMP9 expression were observed in CaCl2-induced AAA wall in miR-33-/- mice and these reduction were accompanied by reduced MCP-1 expression. Peritoneal MΦ from miR-33-/- mice showed reduced M1 marker genes and MMP9 expressions via JNK inactivation. VSMCs from miR-33-/- mice showed reduced MCP-1 expression by p38 MAPK attenuation. Moreover, HDL-C derived from miR-33-/- mice reduced MMP9 expression in MΦ and MCP-1 expression in VSMCs. Bone marrow (BM) transplantation experiment indicated that miR-33 deficient BM cells ameliorated AAA formation in the wild-type recipient. It was also shown that miR-33 deficiency in the recipient mice also contributed the inhibition of AAA formation. Thus, not only BM cells but also other recipient factors such as changes of VSMCs character and elevated HDL-C might have distinct beneficial effects on AAA formation in miR-33-/- mice.
Conclusions: These data strongly suggest that inhibition of miR-33 is a strategy for treating AAA.
Author Disclosures: T. Nakao: None. T. Horie: None. O. Baba: None. M. Nishiga: None. T. Nishino: None. H. Nishi: None. M. Izuhara: None. S. Usami: None. N. Nakaseki: None. S. Koyama: None. Y. Ide: None. T. Kimura: None. K. Ono: None.
- © 2016 by American Heart Association, Inc.