Gold nanoparticle-based miR155 antagonist macrophage delivery restores the cardiac function in ovariectomized diabetic mouse model

Abstract

Chengming Jia,1,2,* Hui Chen,3,* Mengying Wei,2,* Xiangjie Chen,4 Yajun Zhang,5 Liang Cao,1 Ping Yuan,1 Fangyuan Wang,1 Guodong Yang,2 Jing Ma1 1Department of Chinese Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, China; 2Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi’an, China; 3Department of Plastic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China; 4Department of Mathematics, Southeast University, Nanjing, China; 5Department of Ultrasound Diagnosis, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China *These authors contributed equally to this work Abstract: Diabetic cardiomyopathy is a common disease in postmenopausal women, in whom the estrogen deficiency aggravates the pathology. In this study, we have found that estrogen deficiency due to ovariectomy aggravates the inflammation in the hearts of diabetic mice, as depicted by excessive proinflammatory type 1 macrophages (M1) over anti-inflammatory type 2 macrophages (M2). Accordingly, an additional increase of reactive oxygen species, cell apoptosis, cardiac hypertrophy, and fibrosis was observed in the hearts of ovariectomized diabetic mice, in comparison with the diabetes-only group. Significantly, miR155, a potent promoter of M1 polarization, was found to be additionally enhanced in the macrophages and hearts by ovariectomy. Tail vein injection of miR155-AuNP, in which thiol-modified antago-miR155 was covalently conjugated with gold nanoparticle (AuNP), preferentially delivered the nucleic acids into the macrophages via phagocytosis. Together with the increased M2 ratio and reduced inflammation, in vivo delivery of antago-miR155 reduced cell apoptosis and restored the cardiac function. The restoration efficacy of miR155-AuNP was much better than general macrophage depletion by clodrosome. In summary, we revealed that M1/M2 imbalance contributes to the aggravated cardiomyopathy in ovariectomized diabetic mice, and therapeutically reducing miR155 in macrophages by AuNP serves as a promising strategy in improving cardiac function. Keywords: gold nanoparticle, miR155, cardiac function, macrophage, ovariectomized diabetic mouse model, targeted delivery

Keywords

• Gold nanoparticle
• miR155
• cardiac function
• macrophage
• ovariectomized diabetic mouse model