Maternal High-Fat Diet Promotes Abdominal Aortic Aneurysm Expansion in Adult Offspring by Epigenetic Regulation of IRF8-Mediated Osteoclast-like Macrophage Differentiation.

Noriyuki Wakana,Satoaki Matoba,Naotoshi Wada,Daisuke Kami,Hiroyuki Yamada,Makoto Saburi,Takeshi Sugimoto,Daisuke Miyawaki,Takehiro Ogata,Hiroshi Kubota,Shinichiro Motoyama

doi:10.3390/cells10092224

Noriyuki Wakana, Satoaki Matoba + Show 9 more

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https://doi.org/10.3390/cells10092224

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Journal: Cells	Publication Date: Aug 27, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Kyoto Prefectural University of Medicine

Abstract

Maternal high-fat diet (HFD) modulates vascular remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) development. Female wild-type mice were fed an HFD or normal diet (ND). AAA was induced in eight-week-old pups using calcium chloride. Male offspring of HFD-fed dams (O-HFD) showed a significant enlargement in AAA compared with the offspring of ND-fed dams (O-ND). Positive-staining cells for tartrate-resistant acid phosphate (TRAP) and matrix metalloproteinase (MMP) activity were significantly increased in O-HFD. The pharmacological inhibition of osteoclastogenesis abolished the exaggerated AAA development in O-HFD. The in vitro tumor necrosis factor-α-induced osteoclast-like differentiation of bone marrow-derived macrophages showed a higher number of TRAP-positive cells and osteoclast-specific gene expressions in O-HFD. Consistent with an increased expression of nuclear factor of activated T cells 1 (NFATc1) in O-HFD, the nuclear protein expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor, were much lower, with significantly increased H3K27me3 marks at the promoter region. The enhancer of zeste homolog 2 inhibitor treatment restored IRF8 expression, resulting in no difference in NFATc1 and TRAP expressions between the two groups. Our findings demonstrate that maternal HFD augments AAA expansion, accompanied by exaggerated osteoclast-like macrophage accumulation, suggesting the possibility of macrophage skewing via epigenetic reprogramming.

Highlights

IntroductionEpigenetic modifications have emerged as a novel therapeutic approach for cardiovascular diseases (CVDs), as well as metabolic disorders and malignancies [7,8,9]
Given that Abdominal aortic aneurysm (AAA) development is closely related with the augmented accumulation of macrophages and consequent inflammatory response in the adventitia [15,16], it is likely that the epigenetic reprogramming of monocytes/macrophages via maternal high-fat diet (HFD) plays a critical role in AAA development in the offspring
The low-density lipoprotein cholesterol levels were significantly higher in O-HFD, while the high-density lipoprotein cholesterol levels were lower in OHFD compared with those in O-normal diet (ND) (Supplementary Figure S1)

Summary

Introduction

Epigenetic modifications have emerged as a novel therapeutic approach for cardiovascular diseases (CVDs), as well as metabolic disorders and malignancies [7,8,9]. We have shown that maternal high-fat diet (HFD). Intake leads to atherosclerosis development and HFD-induced insulin resistance in offspring via 4.0/). The augmented macrophage-mediated inflammatory response [10,11]; the underlying epigenetic mechanisms have not been fully elucidated. Given that AAA development is closely related with the augmented accumulation of macrophages and consequent inflammatory response in the adventitia [15,16], it is likely that the epigenetic reprogramming of monocytes/macrophages via maternal HFD plays a critical role in AAA development in the offspring

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