Effective Delivery of Hypertrophic MiRNA Inhibitor by Cholesterol-Containing Nanocarriers for Preventing Pressure Overload Induced Cardiac Hypertrophy

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2019 Jun 11

PMID 31179215

Citations 15

Authors

Ying Zhi

Chen Xu

Dandan Sui

Jie Du

Fu-Jian Xu

Yulin Li

Affiliations

Soon will be listed here.

Abstract

Persistent cardiac hypertrophy causes heart failure and sudden death. Gene therapy is a promising intervention for this disease, but is limited by the lack of effective delivery systems. Herein, it is reported that CHO-PGEA (cholesterol (CHO)-terminated ethanolamine-aminated poly(glycidyl methacrylate)) can efficiently condense small RNAs into nanosystems for preventing cardiac hypertrophy. CHO-PGEA contains two features: 1) lipophilic cholesterol groups enhance transfection efficiency in cardiomyocytes, 2) abundant hydrophilic hydroxyl groups benefit biocompatibility. miR-182, which is known to downregulate forkhead box O3, is selected as an intervention target and can be blocked by synthetic small RNA inhibitor of miR-182 (miR-182-in). CHO-PGEA can efficiently deliver miR-182-in into hearts. In the mice with aortic coarctation, CHO-PEGA/miR-182-in significantly suppresses cardiac hypertrophy without organ injury. This work demonstrates that CHO-PGEA/miRNA nanosystems are very promising for RNA-based therapeutics to treat heart diseases.

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References

Nie J, Qiao B, Duan S, Xu C, Chen B, Hao W . Unlockable Nanocomplexes with Self-Accelerating Nucleic Acid Release for Effective Staged Gene Therapy of Cardiovascular Diseases. Adv Mater. 2018; 30(31):e1801570. DOI: 10.1002/adma.201801570. View

Li N, Hwangbo C, Jaba I, Zhang J, Papangeli I, Han J . miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart. Sci Rep. 2016; 6:21228. PMC: 4758045. DOI: 10.1038/srep21228. View

Li Z, Song Y, Liu L, Hou N, An X, Zhan D . miR-199a impairs autophagy and induces cardiac hypertrophy through mTOR activation. Cell Death Differ. 2015; 24(7):1205-1213. PMC: 5520159. DOI: 10.1038/cdd.2015.95. View

Zhou J, Liu J, Cheng C, Patel T, Weller C, Piepmeier J . Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery. Nat Mater. 2011; 11(1):82-90. PMC: 4180913. DOI: 10.1038/nmat3187. View

Feng H, Ouyang W, Liu J, Sun Y, Hu R, Huang L . Global microRNA profiles and signaling pathways in the development of cardiac hypertrophy. Braz J Med Biol Res. 2014; 47(5):361-8. PMC: 4075303. DOI: 10.1590/1414-431x20142937. View

Tang T, Gao M, Hammond H . Prospects for gene transfer for clinical heart failure. Gene Ther. 2012; 19(6):606-12. PMC: 3555515. DOI: 10.1038/gt.2012.36. View

Thiel C, Nix M . Efficient transfection of primary cells relevant for cardiovascular research by nucleofection. Methods Mol Med. 2006; 129:255-66. DOI: 10.1385/1-59745-213-0:255. View

Schumacher S, Gao E, Cohen M, Lieu M, Chuprun J, Koch W . A peptide of the RGS domain of GRK2 binds and inhibits Gα(q) to suppress pathological cardiac hypertrophy and dysfunction. Sci Signal. 2016; 9(420):ra30. PMC: 5015886. DOI: 10.1126/scisignal.aae0549. View

Read M, Singh S, Ahmed Z, Stevenson M, Briggs S, Oupicky D . A versatile reducible polycation-based system for efficient delivery of a broad range of nucleic acids. Nucleic Acids Res. 2005; 33(9):e86. PMC: 1140087. DOI: 10.1093/nar/gni085. View

10.

Zhu Y, Zhang C, Chen B, Chen R, Guo A, Hong J . Cholesterol is required for maintaining T-tubule integrity and intercellular connections at intercalated discs in cardiomyocytes. J Mol Cell Cardiol. 2016; 97:204-12. PMC: 5002380. DOI: 10.1016/j.yjmcc.2016.05.013. View

11.

Kim C, Lee H, Gupta N, Ramachandran S, Kaushik I, Srivastava S . Role of Forkhead Box Class O proteins in cancer progression and metastasis. Semin Cancer Biol. 2017; 50:142-151. PMC: 5794649. DOI: 10.1016/j.semcancer.2017.07.007. View

12.

Chen J, Normand S, Wang Y, Krumholz H . National and regional trends in heart failure hospitalization and mortality rates for Medicare beneficiaries, 1998-2008. JAMA. 2011; 306(15):1669-78. PMC: 3688069. DOI: 10.1001/jama.2011.1474. View

13.

Schips T, Wietelmann A, Hohn K, Schimanski S, Walther P, Braun T . FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res. 2011; 91(4):587-97. DOI: 10.1093/cvr/cvr144. View

14.

Huang Z, Chen J, Seok H, Zhang Z, Kataoka M, Hu X . MicroRNA-22 regulates cardiac hypertrophy and remodeling in response to stress. Circ Res. 2013; 112(9):1234-43. PMC: 3720677. DOI: 10.1161/CIRCRESAHA.112.300682. View

15.

Bang C, Batkai S, Dangwal S, Gupta S, Foinquinos A, Holzmann A . Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy. J Clin Invest. 2014; 124(5):2136-46. PMC: 4001534. DOI: 10.1172/JCI70577. View

16.

Brunet A, Bonni A, Zigmond M, Lin M, Juo P, Hu L . Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999; 96(6):857-68. DOI: 10.1016/s0092-8674(00)80595-4. View

17.

Li R, Wu Y, Zhi Y, Yang X, Li Y, Xua F . PGMA-Based Star-Like Polycations with Plentiful Hydroxyl Groups Act as Highly Efficient miRNA Delivery Nanovectors for Effective Applications in Heart Diseases. Adv Mater. 2016; 28(33):7204-12. DOI: 10.1002/adma.201602319. View

18.

Alexander M, Hu R, Runtsch M, Kagele D, Mosbruger T, Tolmachova T . Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 2015; 6:7321. PMC: 4557301. DOI: 10.1038/ncomms8321. View

19.

Han M, Yang Z, Sayed D, He M, Gao S, Lin L . GATA4 expression is primarily regulated via a miR-26b-dependent post-transcriptional mechanism during cardiac hypertrophy. Cardiovasc Res. 2012; 93(4):645-54. PMC: 3291090. DOI: 10.1093/cvr/cvs001. View

20.

Brown R . Medicine. A reinnervating microRNA. Science. 2009; 326(5959):1494-5. DOI: 10.1126/science.1183842. View