冷诱导RNA结合蛋白在病理性心肌重构中的作用与机制

Pathological cardiac remodeling is prerequisite for chronic heart failure. The over-activation of neurohormonal signaling is one key factor for the progression of the pathological process. We propose that swift effectors to stress within cardiomyocytes may play a role in the feedback regulation on neurohormonal signaling. Thus, we conducted a preliminary study to explore the potential role of cold-inducible RNA-binding protein (CIRP), an effector sensitive to pan-stressors, in pathological cardiac remodeling. We found that knockout of Cirp in the rat did not affect body development and growth and the structure and function of the heart under basal conditions, but facilitate the development of pathological cardiac remodeling induced by persistent -adrenergic stress, suggesting that CIRP plays an important role in the neurohormonal signaling overactivation-induced pathological cardiac remodeling. The proposal based on the preliminary evidences aims to explore the effects and the related mechanisms for CIRP in pathological cardiac remodeling induced by neurohormonal signaling overactivation or the related conditions, initially define the significance of CIRP in the intervention of pathological cardiac remodeling, and validate the potential relation of CIRP deficiency to chronic heart failure in human. The project should open a new avenue for the posttranscriptional regulation on pathological cardiac remodeling.

病理性心肌重构是慢性心力衰竭发生的前提。神经-体液过度激活是病理性心肌重构发生的关键之一。我们假设，心肌细胞内应激敏感分子可能反馈调控上述神经-体液应激反应，从而影响病理性心肌重构的发生发展。为此，我们初步研究了作为重要应激敏感分子的冷诱导RNA结合蛋白（CIRP）。我们发现：CIRP敲除并不影响大鼠的生长发育和生理情况下的心脏结构功能；而在肾上腺素能应激的情况下，CIRP敲除突出地从发生时间和严重程度上易化了大鼠病理性心肌重构现象。提示，CIRP在神经-体液过度激活诱导的病理性心肌重构中发挥着重要的调控作用。本项目拟在前期研究的基础上，系统性探索CIRP在神经-体液过度激活诱导或者相关的病理性心肌重构中的作用和信号调控通路；初步证明CIRP在病理性心肌重构干预中的意义；验证CIRP缺陷与人类慢性心力衰竭的关系。本研究有望从转录后调控这个新的视角开启病理性心肌重构研究新方向。

病理性心肌重构是慢性充血性心力衰竭发生的前提。神经-体液过度激活是病理性心肌重构发生的关键机制之一。我们假设，心肌细胞内应激敏感分子可能反馈调控上述神经-体液应激反应带来的病理性心肌重构的发生发展。本项目探索了作为应激敏感分子的冷诱导RNA结合蛋白（CIRP）与神经-体液过度激活相关的病理性心肌重构和心律失常的关系。我们意外地发现，CIRP并不影响神经-体液等因素诱导的心脏病理性重构。相反，我们发现CIRP可以通过转录后调控窦房结细胞内IV型磷酸二酯酶（PDE4）的表达，参与交感应激下的窦房结起搏功能和心率的交感反应性调控。CIRP缺失通过cAMP-PKA信号通路增加了钙掌控蛋白的磷酸化水平及cAMP浓度，从而引发应激带来的心率的过度交感反应。不但如此，我们还发现CIRP缺失可以特异性增加心房心肌细胞电压依赖性钾离子通道（Kv）功能，缩短了心房肌动作电位时程，进而导致应激情况下房颤的易感性增加。机制上，我们从在体及体外层面均发现CIRP敲除增加了Kv1.5，Kv4.2，Kv4.3的蛋白表达量，但是不影响其mRNA表达量，说明CIRP在转录后层面调控了这三个钾通道基因的表达。进一步的分子实验证实，CIRP是通过与这些钾通道的mRNA的3`-UTR区直接结合的方式调控了这些基因的表达。本项目鉴定出一个心率稳定因子和房颤易感调控分子，为窦性心律失常和房颤的防治提供了潜在的靶点。本项目合计发表标注受项目资助的SCI论文16篇，代表性研究成果发表在《Circulation Research》等刊物上。