Abstract 15350: Progressive Aortic Dilatation is Regulated by the mir-17 Cluster
Introduction: Ascending aortic aneurysms dilate due to activation of matrix metalloproteinase (MMPs), and matrix disruption. MicroRNAs (miRNAs) may contribute to the pathogenesis of aortic dilatation, but the specific miRNAs responsible have not been determined. We aimed to identify the miRNAs associated with progressive aortic dilation in patients with Marfan syndrome and bicuspid aortic valve (BAV) aortopathy.
Methods and Results: Aortic tissue samples (~1х1cm) were collected from the dilated aneurysmal segment and adjacent nondilated segment which appeared normal at aortic surgery. The nondilated segments represent the early stages of aortic matrix degradation (before dilatation) and the dilated segment represents the late stage after aortic remodeling. Fourteen sample pairs were collected from BAV patients and 8 pairs from Marfan patients. miRNA levels were determined by Affymetrix GeneChip miRNA 3.0 Array for miRNA profiling. miRNA expression in the nondilated were compared to the dilated segments. The top 20 miRNAs with the most dramatic up- and downregulation were identified and further validated by real-time PCR. A 1.5-2-fold increase in expression of the miR-17 cluster (miR-17, miR-106a/b, miR-20a/b, miR-93) was detected by real-time PCR in nondilated compared to dilated aortic segments (P < 0.05). Next, we examined the targets of the miR-17 cluster, the tissue inhibitors of MMPs (TIMP) 2 and 3 by Western blot. The nondilated segments had significantly lower TIMP 2 and 3 protein levels compared to the dilated segments (P < 0.05). MMP2 activity, determined by zymography, was increased in the nondilated aortic segments compared with the dilated segments (P < 0.05). In patients with Marfan, but not in BAV patients, phospho-AKt-s473 and total AKt (an important cell survival factor) were significantly decreased in the nondilated compared with dilated aortic segments.
Conclusions: The nondilated aortic regions adjacent to aortic aneurysms had early signs of matrix degradation associated with upregulation of the miR-17 cluster in both BAV and Marfan syndrome, although some of the downstream pathways were different in the two groups. Targeting the miR-17 cluster may be a novel therapeutic strategy to prevent progressive aortic dilation.
Author Disclosures: J. Wu: None. J. Guo: None. S. Li: None. K. Tsang: None. L. Tumiati: None. C.M. David: None. J. Bos: None. M. Ouzounian: None. T.M. Yau: None. T.E. David: None. R.D. Weisel: None. R. Li: None.
- © 2014 by American Heart Association, Inc.