Stabley John N, Towler Dwight A
From the Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX.
Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):205-217. doi: 10.1161/ATVBAHA.116.306258. Epub 2016 Dec 22.
Diabetes mellitus increasingly afflicts our aging and dysmetabolic population. Type 2 diabetes mellitus and the antecedent metabolic syndrome represent the vast majority of the disease burden-increasingly prevalent in children and older adults. However, type 1 diabetes mellitus is also advancing in preadolescent children. As such, a crushing wave of cardiometabolic disease burden now faces our society. Arteriosclerotic calcification is increased in metabolic syndrome, type 2 diabetes mellitus, and type 1 diabetes mellitus-impairing conduit vessel compliance and function, thereby increasing the risk for dementia, stroke, heart attack, limb ischemia, renal insufficiency, and lower extremity amputation. Preclinical models of these dysmetabolic settings have provided insights into the pathobiology of arterial calcification. Osteochondrogenic morphogens in the BMP-Wnt signaling relay and transcriptional regulatory programs driven by Msx and Runx gene families are entrained to innate immune responses-responses activated by the dysmetabolic state-to direct arterial matrix deposition and mineralization. Recent studies implicate the endothelial-mesenchymal transition in contributing to the phenotypic drift of mineralizing vascular progenitors. In this brief overview, we discuss preclinical disease models that provide mechanistic insights-and point to challenges and opportunities to translate these insights into new therapeutic strategies for our patients afflicted with diabetes mellitus and its arteriosclerotic complications.
糖尿病日益困扰着我们老龄化且代谢紊乱的人群。2型糖尿病及前驱代谢综合征构成了绝大部分疾病负担，在儿童和老年人中愈发普遍。然而，1型糖尿病在青春期前儿童中也呈上升趋势。如此一来，我们的社会如今面临着一波沉重的心脏代谢疾病负担。代谢综合征、2型糖尿病和1型糖尿病中动脉粥样硬化钙化均增加，损害了传导血管的顺应性和功能，从而增加了患痴呆症、中风、心脏病发作、肢体缺血、肾功能不全和下肢截肢的风险。这些代谢紊乱情况的临床前模型为动脉钙化的病理生物学提供了见解。骨形态发生蛋白-翼状螺旋转录因子信号转导通路中的骨软骨生成形态发生素以及由Msx和Runx基因家族驱动的转录调控程序与先天免疫反应相关联，这些反应由代谢紊乱状态激活，以指导动脉基质沉积和矿化。最近的研究表明，内皮-间充质转化促成了矿化血管祖细胞的表型漂移。在本简要概述中，我们讨论了提供机制见解的临床前疾病模型，并指出了将这些见解转化为针对患有糖尿病及其动脉硬化并发症患者的新治疗策略所面临的挑战和机遇。
