Metabolic control of vascular smooth muscle cell plasticity

血管平滑肌细胞(SMC)的去分化为合成SMC，这是许多 闭塞性血管疾病，与以有氧代谢增加为特征的代谢转换有关 糖酵解，也促进甲氧戊酸代谢，减少葡萄糖氧化和增加脂肪酸 氧化。然而，环境信号和代谢重新编程之间的分子联系仍然存在。 人们对此知之甚少。我们的前期研究表明，细胞周期蛋白依赖性激酶8(CDK8)是一种主要的调控因子。 血管SMC脱分化对血管闭塞后内膜增生的代谢调控。 机制研究发现CDK8控制SREBP2(类固醇调节元件结合 因子-2)转录促进甲羟戊酸代谢，促进蛋白香叶基香叶化， 导致血管SMC去分化。因此，我们提出了一种新的范式，其中CDK8控制着 甲羟戊酸代谢促进血管内皮细胞脱分化的研究 血管内膜增生，从而导致闭塞性血管疾病。我们将检验这一假设，并 CDK8调控血管SMC去分化代谢的分子机制 2个具体目标：目标1将确定CDK8在血管SMC脱分化为合成SMC过程中的中介作用 用于血管闭塞的内膜增生的SMC；Aim 2将确定潜在的分子 CDK8调控甲羟戊酸代谢的分子网络机制 血管SMC脱分化为合成SMC所需的蛋白质香叶素合成途径 SMC导致血管闭塞的血管内膜增生。这项提案将提供第一次评估 CDK8介导的闭塞血管病变的形成和定义一条新的闭塞血管通路 先前未知的CDK8操作的血管代谢重编程所介导的重塑 SMC脱分化，从而为血管SMC可塑性的研究和发展提供了新的思路 对闭塞性血管疾病的创新和有效的治疗方法。

The dedifferentiation of vascular smooth muscle cells (SMCs) into synthetic SMCs, a hallmark of many occlusive vascular diseases, is associated with a metabolic switch that is characterized by increased aerobic glycolysis, which also fuels mevalonate metabolism, decreased glucose oxidation and increased fatty acid oxidation. However, the molecular links between environmental cues and the metabolic reprogramming remain poorly understood. Our pilot studies revealed that cyclin dependent kinase 8 (CDK8) is a master regulator of the metabolic control of vascular SMC dedifferentiation for intimal hyperplasia toward vascular occlusion. Mechanistic investigations uncovered that CDK8 controls the SREBP2 (sterol regulatory element binding factor-2)-operated transcription to promote the mevalonate metabolism for protein geranylgeranylation, which drives the vascular SMC dedifferentiation. Thus, we propose a novel paradigm in which CDK8 controls the mevalonate metabolism for protein geranylgeranylation to promote the dedifferentiation of vascular SMCs for intimal hyperplasia, thereby contributing to occlusive vascular disease. We will test this hypothesis and delineate the molecular mechanisms of CDK8-operated metabolic control of vascular SMC dedifferentiation by 2 specific aims: Aim 1 will establish a mediator role of CDK8 in vascular SMC dedifferentiation into synthetic SMCs for intimal hyperplasia toward vascular occlusion; Aim 2 will determine the underlying molecular mechanisms with a focus on the molecular network by which CDK8 operates the mevalonate metabolism pathway for protein geranylgeranylation which is required for vascular SMC dedifferentiation into synthetic SMCs leading to intimal hyperplasia toward vascular occlusion. This proposal will provide the first assessment of CDK8-mediated occlusive vascular lesion formation and define a novel pathway of occlusive vascular remodeling that is mediated by previously unrecognized CDK8-operated metabolic reprogramming for vascular SMC dedifferentiation, thus shedding light on the study of vascular SMC plasticity as well as the development of innovative and effective therapeutic approaches for occlusive vascular disease.