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

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.

The Role of Leukocytes in Diabetic Cardiomyopathy

“…A more recent study similarly reported alterations in streptozotocin-treated mouse hearts, including enhanced pro-inflammatory cytokine expression, fibrosis and decreased function that was associated with macrophage accumulation, but notably highlighted the negative impact of estrogen deficiency on these processes through the use of ovariectomized female mice ( Jia et al, 2017 ). These changes were also associated with increased expression of pro-M1/anti-M2 macrophage miR155.…”

Noncoding RNAs as therapeutic targets in atherosclerosis with diabetes mellitus

“…Interestingly, in diabetic mice, miR‐155 is associated with macrophage‐mediated inflammation . miR‐155 is a potent promoter of M1 polarization, and it was found to be additionally enhanced in the macrophages.…”

“…miR‐155 is a potent promoter of M1 polarization, and it was found to be additionally enhanced in the macrophages. Cheng Ming Jia et al using gold nanoparticles (AuNPs) preferentially delivered antago‐miR‐155 to macrophages by phagocytosis. The results showed that miR‐155 was highly expressed in diabetic mice, and AuNP‐mediated cell‐specific inhibition of miR‐155 expression in macrophages promotes M2 polarization, represses inflammation, and thus restores the cardiac function.…”

“…P53 plays a crucial role in atherosclerosis lesion development and remodeling, and macrophage-specific p53 deficiency stimulates cellular proliferation and increases vulnerable-appearing phenotype of lesions in a mouse model of familial hypercholesterolemia 60. This provides further issues with the use of miR-125b as a diagnostic tool and therapeutic targets.Interestingly, in diabetic mice, miR-155 is associated with macrophage-mediated inflammation 88. miR-155 is a potent promoter of M1 polarization, and it was found to be additionally enhanced in the macrophages.…”

Recent progress in microRNA-based delivery systems for the treatment of human disease

“…Functional groups such as thiol and amino groups can be easily attached to the surface of AuNPs, and these chemically modified AuNPs have been employed as miRNA vehicles [62]. Jia et al reported the covalent conjugation of thiol-modified antagomir-miRNA-155 to AuNPs, and the administration of miRNA-155-AuNPs via tail vein injection promoted M2 macrophage polarization, reduced inflammatory mediators and ultimately recovered cardiac function in an ovariectomized (OVX) diabetic murine model [63].…”