Abstract 652: MicroRNA-29b Mediates the Chronic Inflammatory Response in Radiotherapy-induced Vascular Disease

Abstract

Radiotherapy is an established therapeutic method in many different cancer types. Its success raises a new problem, namely radiotherapy-induced vascular disease (vRTx), which typically manifests as coronary disease, heart failure or carotid stenosis. A chronic inflammatory response likely underlies vRTx, involving complex processes, such as vascular smooth muscle cell de-differentiation, oxidative stress, and ECM remodeling. These processes are tightly regulated and thus far difficult to influence therapeutically. In other diseases, a set of microRNAs (miRs) is known to orchestrate these processes. We hypothesized that they similarly could play a role in vRTx and be targets for treatment or prevention of the disease. We performed qRT-PCR screening of 11 pre-selected miRs, which identified miR-29b as significantly decreased in irradiated arteries collected from patients undergoing free tissue transfer reconstruction, compared with non-irradiated arteries from the same patient (n=15). In a vascular biology context, miR-29b is known as inhibitor of collagen- and ECM associated mRNA targets, and has been shown to play a detrimental role in aneurysm disease and advanced atherosclerotic lesions. Consistent with human tissue data, vascular smooth muscle and endothelial cells in vitro receiving two radiation doses of 2 Gy, showed decreased miR-29b upon 24 hours after exposure. In these irradiated SMCs, miR-29b induction reduced soluble collagen levels, while inhibition further increased them. Array-based tissue gene expression analysis showed that Pentraxin-3 (PTX) and dipeptidyl-peptidase 4 (DPP4), both targets of miR-29b and pivotal in inflammation and adverse wound healing, were downregulated in the same patient cohort. Carotid arteries of Apoe -/- mice treated with miR-29b mimic, 24h before and 24h after irradiation (14 Gy to the upper chest and neck), displayed a downward trend (non-significant) in Ptx3 and Dpp4 gene expression. Our results suggest that miR-29b overexpression therapy could have a place in the prevention of vRTx. To further strengthen this conclusion, additional Apoe -/- mice irradiation experiments are currently ongoing, to further establish PTX3 and DPP4 as mediators of anti-inflammatory and anti-fibrotic strategies.