Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis.
Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis.
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DOI：
10.1371/journal.pone.0246600
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Tabas I
中科院分区：
文献类型：
--
作者：
Ozcan L;Kasikara C;Yurdagul A Jr;Kuriakose G;Hubbard B;Serrano-Wu MH;Tabas I
由不稳定斑块引起的动脉粥样硬化性血管疾病是2型糖尿病（T2 D）受试者发病率和死亡率的主要原因，因此主要的治疗目标是发现也可以促进动脉粥样硬化斑块稳定性的T2 D药物。肥胖小鼠中丝裂原活化蛋白激酶活化蛋白激酶-2（MAPKAPK 2或MK2）的遗传或药物抑制可改善葡萄糖稳态并增强胰岛素敏感性。我们开发了两种新的口服活性小分子MK2抑制剂TBX-1和TBX-2，并测试了它们对高脂西方饮食（WD）喂养的Ldlr-/-小鼠代谢和动脉粥样硬化的影响。首先给Ldlr-/-小鼠喂食WD以允许建立动脉粥样硬化病变，然后用TBX-1或TBX-2处理小鼠。这两种化合物都能改善葡萄糖代谢，降低血浆胆固醇和甘油三酯，但对体重没有影响。最重要的是，这些化合物减少了小鼠主动脉根部病变的病变面积，减轻了斑块坏死，并增加了纤维帽厚度。因此，在高脂饮食和已建立的动脉粥样硬化的临床前模型中，MK2抑制剂改善了代谢，也增强了动脉粥样硬化斑块的稳定性，这表明进一步临床开发以解决与动脉粥样硬化性血管疾病相关的T2 D流行病的潜力。
Atherosclerotic vascular disease resulting from unstable plaques is the leading cause of morbidity and mortality in subjects with type 2 diabetes (T2D), and thus a major therapeutic goal is to discover T2D drugs that can also promote atherosclerotic plaque stability. Genetic or pharmacologic inhibition of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2 or MK2) in obese mice improves glucose homeostasis and enhances insulin sensitivity. We developed two novel orally active small-molecule inhibitors of MK2, TBX-1 and TBX-2, and tested their effects on metabolism and atherosclerosis in high-fat Western diet (WD)-fed Ldlr-/- mice. Ldlr-/- mice were first fed the WD to allow atherosclerotic lesions to become established, and the mice were then treated with TBX-1 or TBX-2. Both compounds improved glucose metabolism and lowered plasma cholesterol and triglyceride, without an effect on body weight. Most importantly, the compounds decreased lesion area, lessened plaque necrosis, and increased fibrous cap thickness in the aortic root lesions of the mice. Thus, in a preclinical model of high-fat feeding and established atherosclerosis, MK2 inhibitors improved metabolism and also enhanced atherosclerotic plaque stability, suggesting potential for further clinical development to address the epidemic of T2D associated with atherosclerotic vascular disease.