Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs.

Abstract Background Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)–related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta. Objectives This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17–related miRNA regulation of TIMP-MMP. Methods To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal. Results Gene expression analyses confirmed increased expression of miR-17–related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-1 7 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression. Conclusions Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17–related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation.