Department of Internal Medicine, Wake Forest School of Medicine, USA.
Department of Internal Medicine, Wake Forest School of Medicine, USA.
Atherosclerosis. 2021 Jul;328:23-32. doi: 10.1016/j.atherosclerosis.2021.05.002. Epub 2021 May 25.
The thiol transferase glutaredoxin 1 controls redox signaling and cellular functions by regulating the S-glutathionylation status of critical protein thiols. Here we tested the hypothesis that by derepressing the expression of glutaredoxin 1, inhibition of histone deacetylase 2 prevents nutrient stress-induced protein S-glutathionylation and monocyte dysfunction and protects against atherosclerosis.
Using both a pharmacological inhibitor and shRNA-mediated knockdown of histone deacetylase 2, we determine the role of this deacetylase on glutaredoxin 1 expression and nutrient stress-induced inactivation of mitogen-activated protein kinase phosphatase 1 activity and monocyte and macrophage dysfunction. To assess whether histone deacetylase 2 inhibition in myeloid cells protects against atherosclerosis, we fed eight-week-old female and male HDAC2LDLR mice and age and sex-matched LysMcreLDLR control mice a high-calorie diet for 12 weeks and assessed monocyte function and atherosclerotic lesion size.
Myeloid histone deacetylase 2 deficiency in high-calorie diet-fed LDLR mice reduced atherosclerosis in males by 39% without affecting plasma lipid and lipoprotein profiles or blood glucose levels but had no effect on atherogenesis in female mice. Macrophage content in plaques of male mice was reduced by 31%. Histone deacetylase 2-deficient blood monocytes from male mice showed increased acetylation on histone 3, and increased Grx1 expression, and was associated with increased MKP-1 activity and reduced recruitment of monocyte-derived macrophages, whereas in females, myeloid HDAC2 deficiency had no effect on Grx1 expression, did not prevent nutrient stress-induced loss of MKP-1 activity in monocytes and was not atheroprotective.
Specific histone deacetylase 2 inhibitors may represent a potential novel therapeutic strategy for the prevention and treatment of atherosclerosis, but any benefits may be sexually dimorphic.
硫转移酶谷胱甘肽过氧化物酶 1 通过调节关键蛋白巯基的 S-谷胱甘肽化状态来控制氧化还原信号和细胞功能。在这里，我们检验了这样一个假设，即通过解除组蛋白去乙酰化酶 2 的表达抑制，可以防止营养应激诱导的蛋白质 S-谷胱甘肽化和单核细胞功能障碍，并预防动脉粥样硬化。
我们使用药理学抑制剂和 shRNA 介导的组蛋白去乙酰化酶 2 敲低，确定这种去乙酰化酶在谷胱甘肽过氧化物酶 1 表达和营养应激诱导的丝裂原活化蛋白激酶磷酸酶 1 活性失活以及单核细胞和巨噬细胞功能障碍中的作用。为了评估髓样细胞中组蛋白去乙酰化酶 2 抑制是否能预防动脉粥样硬化，我们用高脂肪饮食喂养 8 周龄雌性和雄性 HDAC2LDLR 小鼠以及年龄和性别匹配的 LysMcreLDLR 对照小鼠 12 周，并评估单核细胞功能和动脉粥样硬化病变大小。
在高脂肪饮食喂养的 LDLR 小鼠中，髓样细胞组蛋白去乙酰化酶 2 缺乏可使雄性小鼠的动脉粥样硬化减少 39%，而不影响血浆脂质和脂蛋白谱或血糖水平，但对雌性小鼠的动脉粥样形成没有影响。雄性小鼠斑块中的巨噬细胞含量减少了 31%。雄性小鼠的组蛋白去乙酰化酶 2 缺陷性血单核细胞中组蛋白 3 的乙酰化增加，Grx1 表达增加，与 MKP-1 活性增加和单核细胞衍生的巨噬细胞募集减少有关，而在雌性小鼠中，髓样细胞 HDAC2 缺乏对 Grx1 表达没有影响，不能防止营养应激诱导的单核细胞中 MKP-1 活性丧失，也没有动脉粥样硬化保护作用。
特异性组蛋白去乙酰化酶 2 抑制剂可能代表一种预防和治疗动脉粥样硬化的潜在新的治疗策略，但任何益处都可能存在性别差异。
