Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. In addition, miR-29 is a master inhibitor of extracellular matrix gene expression, which may attenuate fibrosis but could also weaken tissue structure. The goal of this study was to test whether miR-29 could be developed as an effective, broad-acting, and safe therapeutic. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in several mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH-NP) injected systemically at 200 μg/kg body weight. miR-29b-CH-NP, injected once every 3 days, significantly attenuated angiotensin II-induced hypertension. In db/db mice, miR-29b-CH-NP treatment for 12 weeks decreased cardiac and renal fibrosis and urinary albuminuria. In uninephrectomized db/db mice, miR-29b-CH-NP treatment for 20 weeks significantly improved myocardial performance index and attenuated proteinuria. miR-29b-CH-NP did not worsen abdominal aortic aneurysm in ApoE knockout mice treated with angiotensin II. miR-29b-CH-NP caused aortic root fibrotic cap thinning in ApoE knockout mice fed a high-cholesterol and high-fat diet but did not worsen the necrotic zone or mortality. In conclusion, systemic delivery of low-dose miR-29b-CH-NP is an effective therapeutic for several forms of cardiovascular and renal disease in mice.