Abstract 7: AntagomiR-762 Prevents and Reverses Angiotensin II Induced Aortic Stiffening

Abstract

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the aortic adventitia. This leads to aortic stiffening, eventually leading to end-organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in mice with angiotensin II (Ang II)-induced HTN. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. This was a direct effect of Ang II, as miR-762 upregulation was not eliminated by lowering blood pressure with hydralazine and hydrochlorothiazide and was increased only 2-fold in DOCA salt HTN. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762 (antagomiR-762). AntagomiR-762 administration did not influence the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, antagomiR-762 administration in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with Ang II for 4 weeks (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + antagomiR-762(last two weeks) [20±1.76 kPa], p<0.0001). Further studies showed that antagomiR-762 reduced mRNA for several collagens and fibronectin and dramatically upregulated collagenases MMP1a, 8 and 13 (Table). Hence, miR-762 plays a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. AntagomiR-762 might represent a new approach to prevent and possibly reverse aortic stiffening and its consequent end-organ damage.