ApoE基因缺乏母鼠高膽固醇血症促進子代動脈粥狀硬化進程之機制研究

Abstract

心血管疾病如動脈粥狀硬化在近年來是廣泛盛行且死亡率高的慢性疾病之一，主要是由長期高脂飲食攝取與組織慢性發炎所導致。現今研究中提到子代在親代母親子宮內或是嬰兒時期受到的某些因素而對於其後來發育與健康程度有長久影響，此為著名「發展規劃」學說。流行病學研究中發現親代母親在懷孕期間的營養過剩或健康情況較差的狀況將會使得子代在成年期罹患代謝性症候群如第二型糖尿病、脂質代謝與心血管疾病的機率大幅增加。目前認為表觀遺傳的調控模式在發展規劃中可能扮演關鍵的角色，但是如何影響子代罹患動脈粥狀硬化病症代謝疾病的分子機制尚未有詳盡的研究。 我們假設親代母體在懷孕及泌乳期間暴露於西方飲食，將透過表觀遺傳的方式促進子代發炎反應，使得罹患動脈粥狀硬化的機會提高。本研究使用脂蛋白缺乏 (ApoE-/-) 母鼠，在懷孕前後透過西方飲食的誘導使之產生高膽固醇血症，再觀察其子代小鼠罹患疾病的嚴重度。我們發現到子代小鼠受到親代高膽固醇血症的影響，增加成年後罹患代謝性症候群及動脈粥狀硬化的機會。親代餵食西式飲食的子代雌鼠血液中促發炎反應的Ly6Chigh單核球數量顯著提升，主動脈中大量表現發炎介質及巨噬細胞相關基因，進而引起血管壁的發炎反應，此外，我們也發現母鼠高膽固醇血脂症也會促進M1巨噬細胞的極化分化，導致血管壁中巨噬細胞/M1促發炎反應巨噬細胞的數量上升進而促進動脈粥狀硬化斑塊的形成。 總結，我們發現親代母鼠在懷孕及泌乳期間持續食用西式飲食，使得子代小鼠透過促進組織慢性發炎的方式來提高動脈粥狀硬化病症的發生率。

Atherosclerosis is one of the chronic inflammatory vascular diseases with high prevalence and mortality worldwide. It is mainly resulted from accumulative uptake of lipid and prolonged chronic inflammation in tissue. Exposure to adverse maternal environment in utero or at infancy stage may permanently influence the development and health later in life. This phenomenon is so called “developmental programming” or “fetal programming”. Epidemiological studies showed that adverse condition such as overnutrition or ill state of mother may increase the risk of cardiovascular diseases and metabolic disorders in adult offspring. However, the mechanisms underlying the increased susceptibility of offspring to atherosclerosis and metabolic diseases are still unclear. We hypothesized that diet-induced maternal hypercholesterolemia increased the susceptibility to atherosclerosis in adult offspring by inflammation. Apolipoprotein E deficient (ApoE-/-) female mice were fed with control diet (CD) or western diet (WD) prior to and throughout pregnancy and lactation. All mice were fed with WD after weaning. We found that offspring from WD-fed dams were more prone to develop metabolic syndrome and atherosclerosis later in life. Offspring from WD-fed dams exhibited an increased percentage of pro-inflammatory Ly6Chigh monocyte in the blood compared with offspring from CD-fed dams. The expression of inflammatory mediators and macrophages were significantly up-regulated in aorta of female offspring from WD-fed dams, suggesting acceleration of vascular inflammation. Moreover, we showed that maternal hypercholesterolemia promoted M1 macrophage polarization. Together, our study showed that maternal hypercholesterolemia promoted the development of atherosclerosis in female offspring through augmenting inflammation.