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Broad-acting therapeutic effects of miR-29b-chitosan on hypertension and diabetic complications. Mol Ther 2022 Nov 02;30(11):3462-3476

Date

08/16/2022

Pubmed ID

35965413

Pubmed Central ID

PMC9637778

DOI

10.1016/j.ymthe.2022.08.007

Scopus ID

2-s2.0-85136662053 (requires institutional sign-in at Scopus site)   13 Citations

Abstract

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.

Author List

Jensen DM, Han P, Mangala LS, Lopez-Berestein G, Sood AK, Liu J, Kriegel AJ, Usa K, Widlansky ME, Liang M

Author

Michael E. Widlansky MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Chitosan
Diabetes Complications
Diabetes Mellitus
Disease Models, Animal
Fibrosis
Humans
Hypertension
Mice
Mice, Inbred Strains
Mice, Knockout, ApoE
MicroRNAs
Thiolester Hydrolases