Abstract 16283: Nicotine-Augmented Abdominal Aortic Aneurysms are Regulated by MicroRNA-29b
More than 90% of patients with an abdominal aortic aneurysm (AAA) report a history of smoking. MicroRNAs (miRs) regulate gene expression on the post-transcriptional level and play crucial roles in vascular integrity. The present study sought to investigate the effect of nicotine on miR-29b and its putative gene targets, and whether this interaction affects AAA disease progression. Experimental AAAs were induced using two established in vivo models, the porcine-pancreatic-elastase infusion model in C57Bl/6 mice, and the angiotensin II-infusion (AngII) model in apoE(-/-) mice. Nicotine or placebo pellets were implanted subcutaneously 7 days prior to AAA induction. Serum cotinine levels in nicotine treated mice were comparable to those found in medium-to-heavy smokers. Abdominal aortic diameters (AAD), as measured by B-mode ultrasound imaging, were significantly increased in nicotine-treated mice after day 14 in both models, and aortic ruptures in the AngII-induced AAA model were significantly more frequent. Microarray analysis demonstrated (and qRT-PCR confirmed) highly significant upregulation for numerous collagen genes, including Col1a1, Col3a1, and Col5a1, at 7 days after AAA induction in aortic tissue of nicotine-treated animals compared to placebo-treated parallel segments in both models. In correspondance, miR-29b transcript levels were significantly increased. In vivo administration of a locked-nucleic-acid (LNA) antagomiR against miR-29b increased collagen gene expression, inducing an early fibrotic response in the abdominal aortic wall compared to scrambled control antagomiR. LNA-anti-miR-29b treatment also resulted in a significant reduction in AAD progression over time in both models, both with and without nicotine, and led to a significant decrease in aortic ruptures in the AngII model. Similar modulation of miR-29b and its target genes were confirmed in aortic tissue samples from human patients (smokers vs. non-smokers, n=5 each) undergoing surgical AAA repair when compared with infrarenal aortic tissue samples from control organ donors (n=7). Regulation of miR-29b expression and its target genes represent potential new therapeutic targets in limiting AAA disease progression and protection from rupture.
- © 2011 by American Heart Association, Inc.