Abstract 20593: miR376c is Down Regulated in Thoracic Aortic Aneurysms in Marfan Syndrome
Thoracic aortic aneurysms (TAA) in Marfan syndrome (MFS) are associated with an increase in TGF-β in the aortic wall. Changes in post-transcriptional modifiers, such as miRNA, can lead to altered expression of signaling proteins. We hypothesized that altered expression of miRNA occur in MFS, leading to aberrant post-transcriptional regulation of gene expression for signaling proteins, such as TGF-β, that interact with the variant fibrillin in MFS. Total RNA was isolated from aortic tissue collected at time of surgery and snap frozen in liquid nitrogen, from 3 MFS patients with aortic dilatation (1F, 2M; Age 36±18yrs; Ao Diameter 47±3mm) and 3 controls (2F, 1M; Age 45±8yrs). The RNA was reverse transcribed with custom primers for 31 pre-selected miRNA, that were chosen from a list of altered miRNA identified on a microarray performed on peripheral blood of patients with MFS. qPCR was performed on the subsequent cDNA using a custom TaqMan® Array Card (ThermoFisher). miRNA expression was considered to be significantly altered if there was >±2 fold change (p<0.05) compared to control. In aorta of MFS patients, miR376c was identified to be significantly down regulated 2.19 fold (p=0.017) (Fig 1). Previous studies in human pluripotent stem cells have shown that miR376c decreases TGF-β signaling by suppressing Smad4. Smad4 in turn down regulates miR376c, demonstrating a reciprocal antagonism. In this study, the decrease in miR376c in MFS aorta may be the result of excessive TGF-β/Smad4 signaling. This may cause further amplification of TGF-β signaling due to the decrease in miR376c-mediated Smad4 suppression. This study provides evidence for adaptive responses at the post-transcriptional level of gene expression which may modulate TGF-β signaling and hence TAA development in Marfan syndrome.
Author Disclosures: E.N. Robertson: None. S.S. Portelli: None. Y. Lu: None. A.G. Sherrah: None. M. Emmani: None. S. Maleki: None. D. Lai: None. M. Vallely: None. M. Wilson: None. P. Bannon: None. M. Kekic: None. C.G. dos Remedios: None. B.D. Hambly: None. R.W. Jeremy: None.
- © 2016 by American Heart Association, Inc.