Abstract P245: Therapeutic Effects Of Mir-29b-Chitosan On Hypertension And Diabetic Complications

Abstract

MicroRNA miR-29 promotes endothelial function in human arterioles in part by targeting LYPLA1 and increasing nitric oxide production. Endothelial dysfunction is common in cardiovascular diseases such as hypertension and diabetic microvascular complications. 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 develop an effective miR-29 therapeutic for multiple cardiovascular diseases using mouse models. Substantial accumulation of miR-29b and effective knockdown of Lypla1 in mouse tissues were achieved using a chitosan-packaged, chemically modified miR-29b mimic (miR-29b-CH) injected systemically at 200 μg/kg body weight. miR-29b-CH, injected once every three days, significantly attenuated angiotensin II-induced hypertension over two weeks (mean arterial pressure of 128 ± 5 vs 149 ± 5 mmHg, N = 7 Scr-CH, 8 miR-29b-CH p<0.05). In db/db mice, miR-29b-CH treatment for 12 weeks decreased cardiac (0.98 ± 0.13 vs 1.55 ± 0.17 % fibrosis) and renal (2.85 ± 0.28 vs 4.85 ± 0.47 % fibrosis) fibrosis and urinary albuminuria 0.0051 ± 0.0004 vs 0.0069 ± 0.0005 albumin/creatinine, N = 12 Scr-CH, 9 miR-29b-CH, p<0.05). In uninephrectomized db/db mice, the miR-29b-CH treatment for 20 weeks significantly improved myocardial performance index (0.36 ± 0.02 vs 0.57 ± 0.05) in addition to attenuating proteinuria (0.015 ± 0.004 vs 0.033 ± 0.005 protein/creatinine) (N = 8 Scr-CH, 8 miR-29b-CH, p<0.05). miR-29b-CH did not worsen abdominal aortic aneurysm in ApoE knockout mice treated with angiotensin II (33.7 ± 8.2 vs 29.8 ± 6.7% increase in suprarenal abdominal aorta diameter from baseline, N = 8 Scr-CH and 7 miR-29b-CH). miR-29b-CH caused aortic root fibrotic cap thinning (13.8 ± 2.5 vs 20.8 ± 1.8 % of total plaque area) in ApoE knockout mice fed a high cholesterol and high fat diet but did not worsen the necrotic zone (15.2 ± 1.4 vs 12.5 ± 1.0 % of total plaque area) or the mortality (11/12 control mice survived until end of study vs 10/12 miR-29b-CH treated, N = 8 Scr-CH, 7 miR-29b-CH). In conclusion, systemic delivery of low dose miR-29b-CH is an effective therapeutic for several forms of hypertension and diabetic complications in mice.