1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.
1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus.
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DOI：
10.1161/circulationaha.109.856070
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发表时间：
2009-08-25
期刊：
影响因子：
37.8
通讯作者：
Bernal-Mizrachi C
中科院分区：
文献类型：
--
作者：
Oh J;Weng S;Felton SK;Bhandare S;Riek A;Butler B;Proctor BM;Petty M;Chen Z;Schechtman KB;Bernal-Mizrachi L;Bernal-Mizrachi C
心血管疾病是糖尿病患者死亡的主要原因。维生素D缺乏与该人群心血管疾病风险增加有关。为了确定维生素D缺乏介导糖尿病患者加速心血管疾病的机制，我们研究了活性维生素D对巨噬细胞胆固醇沉积的影响。我们从76名肥胖、糖尿病、高血压和维生素D缺乏的患者中获得巨噬细胞（25-羟基维生素D < 80 nmol/L）（A组）和4个对照组：维生素D正常的肥胖、糖尿病、高血压患者（组B，n=15），肥胖、非糖尿病、高血压伴维生素D缺乏患者非肥胖、非糖尿病、非高血压患者维生素D缺乏（D组，n=10）或维生素D充足（E组，n=10）。将来自所有组的同一患者的巨噬细胞在维生素D缺乏或1，25-二羟维生素D3（1，25（OH）2D 3）补充的培养基中培养，并暴露于修饰的低密度脂蛋白胆固醇。1，25（OH）2D 3仅通过减少糖尿病患者的乙酰化或氧化低密度脂蛋白胆固醇摄取来抑制泡沫细胞形成。相反，糖尿病患者巨噬细胞中维生素D受体的缺失加速了修饰LDL诱导的泡沫细胞形成。1，25（OH）2D 3下调c-Jun N-末端激酶的活化可降低PPARγ的表达，抑制CD 36的表达，并阻止oxLDL衍生的胆固醇摄取。此外，1，25（OH）2D 3抑制巨噬细胞内质网应激改善胰岛素信号传导，下调SR-A1表达，并阻止oxLDL和AcLDL衍生的胆固醇摄取。这些结果将维生素D受体信号传导减少确定为糖尿病患者泡沫细胞形成增加和心血管疾病加速的潜在机制。
Cardiovascular disease is the leading cause of death among diabetics. Vitamin D deficiency is associated with increased risk of cardiovascular disease in this population. To determine the mechanism by which vitamin D deficiency mediates accelerated cardiovascular disease in patients with diabetes, we investigated the effects of active vitamin D on macrophage cholesterol deposition. We obtained macrophages from 76 obese, diabetic, hypertensive patients with vitamin D deficiency (25-hydroxyvitamin D < 80 nmol/L)(group A) and four control groups: obese, diabetic, hypertensive patients with normal vitamin D (group B, n=15), obese, non-diabetic, hypertensive patients with vitamin D deficiency (group C, n=25), and non-obese, non-diabetic, non-hypertensive patients with vitamin D deficiency (group D, n=10) or sufficiency (group E, n=10). The same patient’s macrophages from all groups were cultured in vitamin D-deficient or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) supplemented media and exposed to modified low-density lipoprotein cholesterol. 1,25(OH)2D3 suppressed foam cell formation by reducing acetylated or oxidized low-density lipoprotein cholesterol uptake in diabetics only. Conversely, deletion of the vitamin D receptor in macrophages from diabetic patients accelerated foam-cell formation induced by modified LDL. 1,25(OH)2D3 downregulation of c-Jun N-terminal kinase activation reduced PPARγ expression, suppressed CD36 expression, and prevented oxLDL-derived cholesterol uptake. In addition, 1,25(OH)2D3 suppression of macrophage endoplasmic reticulum stress improved insulin signaling, downregulated SR-A1expression, and prevented oxLDL and AcLDL-derived cholesterol uptake. These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam-cell formation and accelerated cardiovascular disease in diabetics.