Cellular signaling events in the pathogenesis of arterial stiffening: an approach to identify Cbfa1 (core binding factor alpha1) as a key mediator of vascular remodeling

动脉硬化与衰老和许多疾病状态如高血压、充血性心力衰竭、糖尿病或肾衰竭有关。动脉僵硬度可能是一个重要的病理生理因素，改变/损害宏观和微循环，导致疾病进展。因此，动脉僵硬度增加已被确定为心血管疾病的独立危险因素。因此，动脉硬度的调节代表了许多疾病的有吸引力的治疗目标。然而，目前缺乏针对硬化过程中血管结构异常和血管信号变化的有效治疗方法，血管重塑（即动脉硬化的结构相关性）伴随着基因表达模式的改变和特定细胞信号通路的激活沿着。初步数据表明，转录因子，核心结合因子α 1（Cbfa1）作为动脉硬化的介质的关键作用。该项目是基于这样的假设，即Cbfa1是血管纤维化和动脉硬化的通用调节器。因此，本项目的目的是检验以下假设：1）动脉Cbfa 1表达通常由血管硬化的不同触发因素诱导（例如，机械应力、激素如血管紧张素II或胰岛素、葡萄糖等），2)增强的Cbfa 1活性本身导致血管硬度增加，最后3）Cbfa 1是差异诱导的动脉硬化过程中的关键介质。在一个更一般的方法，除了Cbfa 1表达4）进一步普遍的信号事件在动脉硬化shall be identified.The本项目的结果阐明了一种新的机制，可能是动脉硬化（Cbfa 1信号;假设1 - 3），而且可以确定进一步的潜在目标的治疗干预（假设4）。

Arterial stiffening is associated with ageing and numerous disease states such as hypertension, congestive heart failure, diabetes mellitus or renal failure. Here arterial stiffness may represent a central pathophysiologic factor that alters/impairs macro- and microcirculation resulting in disease progression. In accordance increased arterial stiffness has been identified as an independent risk factor for cardiovascular disease. Consequently modulation of arterial stiffness represents an attractive therapeutic target for a plenty of diseases. However, effective therapies that target the structural abnormalities and changes in vascular signaling that underlie the process of stiffening are currently lacking.Vascular remodeling (i.e. the structural correlate of arterial stiffening) comes along with an altered pattern of gene expression and activation of specific cellular signaling pathways. Preliminary data indicate a critical role of the transcription factor, core binding factor alpha1 (Cbfa1) as a mediator of arterial stiffening.This project is based on the assumption that Cbfa1 is a universal regulator of vascular fibrosis and arterial stiffening. The aim of this project therefore is to test the hypotheses that 1) arterial Cbfa1 expression is commonly induced by diverse triggers of vascular stiffening (e.g., mechanical stress, hormones as angiotensin II or insulin, glucose, etc.), 2) enhanced Cbfa1 activity, per se, results in increased vascular stiffness and finally 3) Cbfa1 is a critical mediator in differentially induced processes of arterial stiffening. In a more general approach apart from Cbfa1 expression 4) further universal signaling events in arterial stiffness shall be identified.The results of the present project elucidate a novel mechanism that may underlie arterial stiffening (Cbfa1 signaling; hypotheses 1-3) and moreover may identify further potential targets for therapeutic intervention (hypothesis 4).