We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.
Production of (S)-.ALPHA.-benzylmalic acid, inhibitor of carboxypeptidase A by actinomycetes.