初探母體5-aza對子代動脈粥狀硬化病程之影響

Abstract

發展規劃指的是當胎兒在早期胚胎發育階段，母體受到外界環境的刺激下，會增加子代成年後罹患心血管及代謝性疾病的風險，表觀遺傳的調控可能參與其中。研究顯示母親孕期間暴露於高膽固醇血症會增加子代成年後罹患胰島素阻抗及動脈粥硬化之風險，且已知心血管疾病與基因組高度甲基化程度有關。故本實驗旨於研究降低母體甲基化程度是否會影響子代罹患動脈粥狀硬化的病程。六週齡大 ApoE 缺陷小鼠以正常飲食或西方飲食誘導，懷孕前及泌乳期間給予甲基轉移酵素抑制劑 5-aza-2'-deoxycytidine (5-aza)或 PBS，子代出生後皆餵食西方飲食。結果發現親代母鼠給予 5-aza 的處理下，其子代雌雄鼠在3週齡斷奶期間，5-aza + CW組別在體重以及血脂濃度都顯著低於 PBS + CW組；子代雄鼠 5-aza + CW 組別相較於 PBS + CW 組有較差的葡萄糖耐受性及胰島素阻抗，但是血管內有較少斑塊的堆積；另外母體施打 5-aza 的子代雌鼠，脾臟細胞有較低比例的 CD8 T-cell 以及巨噬細胞，且降低了其骨髓衍生巨噬細胞 (BMDM) 進行古典活化 (M1) 及發炎反應。 綜合實驗結果可知，母鼠低甲基化程度，可能藉由影響 M1 巨噬細胞的極化分化以及發炎反應來減緩子代成年後罹患動脈粥狀硬化之風險。

In utero and/or early postnatal exposure to specific risk factors is increasingly considered to contribute to cardiovascular diseases in later life. In particular, accumulating evidence indicates that maternal dyslipidmia programs insulin resistance and atherosclerosis in adult offspring. Given that DNA hypermethylation is highly associated with cardiovascular diseases, we aimed to investigate whether alterlations in maternal DNA methylation levels could ameliorate the progression of atherosclerosis in adult offspring. Six-week-old ApoE -/- female mice fed with either a control diet (CD) or a Western diet (WD) were treated with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza) during pregnancy and lactation. Offspring were fed with WD after weaning. We found that 5-aza + CW group at 3 weeks old exhibited lower body weight and serum cholesterol levels than PBS + CW group. In addition, 5-aza + CW male mice displayed impaired glucose tolerance and insulin resistance compared to PBS + CW group. Intriguingly, we found that 5-aza + CW mice had a smaller lesion size than PBS + CW mice. A significant decrease for both CD8+ cells and macrophage cell poplution was observed in the spleen of 5-aza + CW female mice compared with that of PBS + CW females. Moreover, we showed that maternal 5-aza administration was associated with decreased M1 macrophage polarization. Together, our study showed that maternal 5-aza treatment likely ameliorates the development of atherosclerosis in female offspring through influencing macrophge polarization.