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Abstract 320: MicroRNA-133a Attenuates the Development of Thoracic Aortic Aneurysm


 Rationale:
 Thoracic aortic aneurysms (TAA) result from dysregulated remodeling of the vascular extracellular matrix, and may occur as result of altered resident cellular phenotype. MicroRNA-133a is reduced in clinical TAA specimens and plays an inhibitory role in regulation of pathological phenotypic switch of vascular cells. Accordingly, this study tested the hypothesis that miR-133a replacement attenuates the development of TAA.
 
 
 Methods and Results:
 TAA was induced in wild type mice (0.5M CaCl
 2
 application, 15 minutes). Following 4 weeks, aortic diameter was increased compared to sham operated controls (1094 ± 38 vs 654 ± 8 μm; p<0.05, n=7). Copy number of miR-133a, quantitated by ddPCR, was reduced in TAA tissue (0.28 ± 0.04 vs 0.68 ± 0.11 copy per U6; p<0.05 vs control, n=7). While no change in smooth muscle cell specific Desmin nor α-smooth muscle actin were detected, an increase in copy number of the fibroblast specific discoidin domain receptor 2 (DDR2) and smooth muscle cell myosin heavy chain 11 (MYH11) were observed in TAA tissue. Combined, these results are consistent with the emergence of a population of myofibroblasts with TAA development. Accordingly, fibroblasts were isolated from TAA and sham operated control tissues (n=10). Copy number of miR-133a was reduced in TAA fibroblasts (0.41 ± 0.14 vs 1.60 ± 0.43 copy per U6; p < 0.05 vs control). TAA fibroblast phenotype was compared to controls; adhesion was reduced (-0.85±0.02 vs -0.77±0.02), migration was increased (63±4% vs 47±4%), and rate of collagen disk contraction over 7 hours was increased (-12.2±1.6 vs -8.5±1.0) (all values, p<0.05 vs control). Finally, after TAA induction in mice, a single tail vein injection of either a miR-133a overexpression or scrambled sequence (control) lentivirus was performed. Following 4 weeks, miR-133a replacement attenuated TAA development (800 ± 18 μm vs 1016 ± 16 μm; p < 0.05 vs control; n=8).
 
 
 Conclusion:
 Aortic fibroblast phenotype is altered during TAA progression, and miR-133a replacement attenuates the development of TAA in a murine model. These unique findings suggest stable alterations in aortic fibroblasts may be associated with pathological extracellular matrix remodeling, and regulation by miR-133a may lead to a novel therapeutic strategy.
