Abstract 16004: Nicotine Accelerates the Expansion of Abdominal Aortic Aneurysms in Mice; A Potential Role for miR-21 and miR-26a
Abdominal aortic aneurysms (AAA) are more closely associated with cigarette smoking than any other tobacco-related disease except lung cancer. Nearly all AAA patients (>90%) relate to a history of smoking. microRNAs (miRs) regulate gene expression on the post-transcriptional level and play a crucial role in cardiovascular diseases. The purpose of the present study was to investigate the effect of nicotine on different miRs and their potential role in AAA disease progression. Either nicotine or placebo pellets were implanted subcutaneously 7 days prior to AAA induction in C57BL/6 mice. Experimental AAA was established by using the AAA-elastase infusion model. Growth of AAAs was serially monitored by B-mode ultrasound imaging. Expression levels of miRs and their putative gene targets were determined by using microarray and real time-PCR techniques. Cotinine levels in serum of nicotine treated mice were comparable to those found in medium to heavy smokers. The abdominal aortic diameter was significantly increased in nicotine treated mice after 14 days. Microarray analysis demonstrated and rt-PCR confirmed an upregulation for miR-21 (9.69 fold) and miR-26a (5.76 fold) in aortic tissue of nicotine treated mice as compared to placebo. Upregulation of miR-21 and miR-26a led to a decrease in expression of the PTEN (phosphatase and tensin homolog) gene, which is a key regulator in vascular smooth muscle cell proliferation and apoptosis. Regulation of PTEN by miR-21 and -26a was furthermore evaluated in nicotine treated human aortic smooth muscle cells (hASMC). Decreased PTEN expression was restored when accordant antagomirs against miR-21 and -26a were used simultaneously. Preliminary in vivo results with antagomirs against both miRs reduced significantly the aneurysm size in nicotine treated mice with experimentally induced AAAs. The present study investigated the effect of nicotine on different miRs and their potential role in progressing AAAs. miR-21 and miR-26a were significantly upregulated in nicotine treated mice. Upregulation of these miRs contributed to an extensive increase of AAA growth via downregulation of the PTEN gene. Antagomirs against miR-21 and -26a will potentially lead to new therapeutic targets to limit AAA disease progression.
- © 2010 by American Heart Association, Inc.