Faculty Collaboration Database

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)   2 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

Authors

Alison J. Kriegel PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Mingyu Liang PhD Vice Chair, Center Director, Professor in the Physiology department at Medical College of Wisconsin
Michael E. Widlansky MD Associate 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