期刊
BIOMATERIALS
卷 34, 期 31, 页码 7790-7798出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2013.06.051
关键词
Nanoparticles; Macrophages; Myocardial infarction; Gene expression; Gene silencing
资金
- National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268201000043C, HL090601]
Myocardial infarction (MI) is the most common cause of heart failure (HF), the leading cause of death in the developed world. Oxidative stress due to excessive production of reactive oxygen species (ROS) plays a key role in the pathogenesis of cardiac remodeling leading to HF. NADPH oxidase with Nox2 as the catalytic subunit is a major source for cardiac ROS production. Nox2-NADPH expression is significantly increased in the infarcted myocardium, primarily in neutrophils, macrophages and myocytes. Moreover, mice lacking the Nox2 gene are protected from ischemic injury, implicating Nox2 as a potential therapeutic target. RNAi-mediated gene silencing holds great promise as a therapeutic owing to its high specificity and potency. However, in vivo delivery hurdles have limited its effective clinical use. Here, we demonstrate acid-degradable polyketal particles as delivery vehicles for Nox2-siRNA to the post-MI heart. In vitro, Nox2-5iRNA particles are effectively taken up by macrophages and significantly knockdown Nox2 expression and activity. Following in vivo intramyocardial injection in experimental mice models of MI, Nox2-siRNA particles prevent upregulation of Nox2 and significantly recovered cardiac function. This study highlights the potential of polyketals as siRNA delivery vehicles to the MI heart and represents a viable therapeutic approach for targeting oxidative stress. (C) 2013 Elsevier Ltd. All rights reserved.
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