Elevated Wall Tension Leads to Reduced miR-133a in the Thoracic Aorta by Exosome Release

• Published in: Journal of the American Heart Association 2019-01, Vol.8 (1), p.e010332-e010332
• Main Authors: Akerman, Adam W, Blanding, Walker M, Stroud, Robert E, Nadeau, Elizabeth K, Mukherjee, Rupak, Ruddy, Jean Marie, Zile, Michael R, Ikonomidis, John S, Jones, Jeffrey A
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - diagnostic imaging; Aorta, Thoracic - metabolism; Aortic Aneurysm, Thoracic - genetics; Aortic Aneurysm, Thoracic - metabolism; Aortic Aneurysm, Thoracic - pathology; Cells, Cultured; Disease Models, Animal; Exome - genetics; exosome secretion; Female; fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation; Humans; hypertension; Immunoblotting; Male; Mice; Mice, Inbred C57BL; microRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; Original Research; RNA, Messenger - genetics; thoracic aorta; vascular biology
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.118.010332

Background Reduced miR-133a was previously found to be associated with thoracic aortic ( TA ) dilation, as seen in aneurysm disease. Because wall tension increases with vessel diameter (Law of Laplace), this study tested the hypothesis that elevated tension led to the reduction of miR-133a in the TA . Methods and Results Elevated tension (1.5 g; 150 mm Hg) applied to murine TA ex vivo reduced miR-133a tissue abundance compared with TA held at normotension (0.7 g; 70 mm Hg). Cellular miR-133a levels were reduced with biaxial stretch of isolated murine TA fibroblasts, whereas smooth muscle cells were not affected. Mechanisms contributing to the loss of miR-133a abundance were further investigated in TA fibroblasts. Biaxial stretch did not reduce primary miR-133a transcription and had no effect on the expression/abundance of 3 micro RNA -specific exoribonucleases. Remarkably, biaxial stretch increased exosome secretion, and exosomes isolated from TA fibroblasts contained more miR-133a. Inhibition of exosome secretion prevented the biaxial stretch-induced reduction of miR-133a. Subsequently, 2 in vivo models of hypertension were used to determine the effect of elevated wall tension on miR-133a abundance in the TA : wild-type mice with osmotic pump-mediated angiotensin II infusion and angiotensin II -independent spontaneously hypertensive mice. Interestingly, the abundance of miR-133a was decreased in TA tissue and increased in the plasma in both models of hypertension compared with a normotensive control group. Furthermore, miR-133a was elevated in the plasma of hypertensive human subjects, compared with normotensive patients. Conclusions Taken together, these results identified exosome secretion as a tension-sensitive mechanism by which miR-133a abundance was reduced in TA fibroblasts.