Abstract 14119: MicroRNAs let-7e, -15a, -196b and -411 Circulating Regulators of Atherosclerotic Abdominal Aortic Aneurysms
Introduction: There is no medical treatment to prevent abdominal aortic aneurysm (AAA) growth and rupture rates. MicroRNAs are crucial in the regulation of cardiovascular disease and represent novel pathways to decrease AAA expansion. The aim of this study was to identify circulating microRNAs associated with AAA.
Methods and Results: In an initial discovery study on whole blood samples from 15 patients with AAA and 10 controls, 754 microRNAs were tested using high throughput real-time quantitative PCR. Thirty-four miRNAs were differentially expressed in AAA compared to controls. Using high throughput digital PCR (OpenArray), expression of the 12 most significant miRNAs was further subjected to validation on both peripheral blood and plasma samples from the same 200 patients (40 controls, 40 peripheral arterial disease (PAD), 40 small AAA (30-54mm), 40 large AAA (>55mm), 40 post-operative).
Analysis of whole blood revealed that in both the discovery and validation studies let-7e (fold change 0.56, P=0.007), miR-15a (fold change 0.45, P=0.012), and miR-196b (fold change 0.44, P<0.001) were all downregulated in AAA, and miR-411 (fold change 5.90, P=0.017) was upregulated in whole blood samples. Mir-196b was also significantly downregulated in plasma samples from the same individuals (fold change 3.75, P=0.022). Neither exclusion of the aneurysm sac through surgical intervention nor aneurysm size altered miRNA profiles. The same miRNAs were also differentially expressed in patients with PAD compared to controls, with no difference between AAA and PAD subjects identified.
Target prediction software (MirWalk) revealed that the AAA associated miRNAs were all regulators of AAA related genes; let-7e (COL1A1, COL1A2, COL3A1, MTHFR, MMP1); miR-15a (DAB2IP, MMP3, MTHFR); miR-196b (COL1A1, COL1A2, COL3A1); miR-411 (MMP12, MMP13, MTHFR).
Conclusions: Circulating levels of let-7e, miR-15a, miR-196b and miR-411 are differentially expressed in patients with AAA compared to healthy controls, with miR-196b also differentially expressed in plasma. Regulation of these miRNAs and their target genes represents a new therapeutic pathway to decrease AAA progression and rupture.
- © 2013 by American Heart Association, Inc.