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 (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.

中文翻译：

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变构MAPKAPK2抑制剂可改善晚期动脉粥样硬化的斑块稳定性

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（T2D）患者发病和死亡的主要原因，因此主要的治疗目标是发现还可以促进动脉粥样硬化斑块稳定性的T2D药物。肥胖小鼠中有丝分裂原激活的蛋白激酶激活的蛋白激酶2（MK2）的遗传或药理抑制作用可改善葡萄糖体内稳态并增强胰岛素敏感性。我们开发了两种新型的口服活性小分子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 ^-/-小鼠的代谢和动脉粥样硬化的影响。LDLR ^-/-首先给小鼠喂WD，以使动脉粥样硬化病变得以建立，然后用TBX-1或TBX-2治疗小鼠。两种化合物都改善了葡萄糖的代谢，降低了血浆胆固醇和甘油三酸酯，而对体重没有影响。最重要的是，这些化合物在小鼠的主动脉根部病变中减少了病变区域，减轻了斑块坏死，并增加了纤维帽厚度。因此，在高脂喂养和已确立的动脉粥样硬化的临床前模型中，MK2抑制剂改善了代谢，并增强了动脉粥样硬化斑块的稳定性，这表明进一步的临床开发潜力可解决与动脉粥样硬化性血管疾病有关的T2D流行。