牵张刺激心室肌细胞离子通道重构及AT1信号通路的调控作用

Half of death in patients with congest heart failure (CHF) were due to sudden cardiac death induced by malignancy ventricular arrhythmia. It was related closely to the electrophysiological characteristic of ventricular cells during heart failure. Ventricular cells were suffered unavoidably by mechanical stretch stimulation when ventricular load increased during heart failure development, which resulted to ventricular remodeling. Ventricular remodeling is an essential element to heart failure which including electrical remodeling, structure remodeling, and contraction remodeling. Ion channel remodeling of ventricular cells is the pivotal mechanism of electrical remodeling which contributed to the high incidence of malignancy ventricular arrhythmia in heart failure patients. Previously studies showed that the activation of angiotensin receptor I type (AT1) attributed to ventricular remolding stimulated by mechanical stretch, and treatment with angiotension converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) may decrease the mortality of CHF patients. However, it is not clear currently that the mortality decreased by ACEI or ARB treatment due to the directly suppression on the malignancy ventricular arrhythmia or not. We plan to explore stretch-induced ion channels remodeling of ventricular myocytes and the regulation of AT1 signal on it by the way of cell culture in vitro and heart failure model in vivo studies, it maybe in favour of the clinical treatment and mechanical exploration of malignancy ventricular arrhythmia and sudden cardiac death in CHF patients.

充血性心力衰竭（CHF）患者临床死亡50％为恶性室性心律失常导致的心源性猝死，这与衰竭心肌细胞电生理特征密切相关。心衰发生、发展不可避免遭受增加的心脏负荷，心肌细胞不可避免受到机械力牵张，导致心室重构。心室重构是心衰发生、发展的基础，心室肌细胞离子通道重构是心室电重构的重要基础，也是衰竭心脏恶性心律失常高发生率的基础。激活血管紧张素受体1型（AT1）是牵张刺激心脏重构的重要机制；ACEI和ARB的应用显著降低心衰患者死亡率。但是，目前尚未明确ACEI和ARB是否通过直接抑制恶性心律失常的发生而降低死亡率。我们将通过培养心室肌细胞牵张模型和在体心衰模型，探讨牵张刺激在心衰心室肌细胞离子通道重构中的作用，以及AT1信号通路在其中的作用。从而可能阐明CHF患者恶性心律失常发生的一个重要病理生理机制，为CHF患者心源性猝死的发生机制和防治提供新的思路和初步理论依据。

心室肌细胞离子通道重构是心室电重构的重要基础，也是充血性心力衰竭（CHF）恶性心律失常高发生率的基础。激活血管紧张素受体1型（AT1）是牵张刺激心脏重构的重要机制。但是，目前尚未明确AT1阻滞是否通过直接抑制恶性心律失常的发生而降低死亡率。本研究采用静态牵张刺激和苯肾上腺素（PE）刺激分别构建培养肥大乳鼠心室肌细胞模型，腹主动脉狭窄构建成年大鼠心室肥大心衰模型，探讨肥大心室肌细胞离子通道重构和AT1信号的调控作用，以及AT1的下游机制。结果显示，无论是在培养肥大心室肌细胞还是在体肥大心室肌细胞，皆通过激活AT1，调控细胞离子通道基因和蛋白表达以及离子通道功能。对AT1激活后心室肌细胞离子通道重构的下游信号通路研究显示，AT1活化进而激活半胱氨酸丰富跨膜成骨蛋白调控因子（Crim1）和钙调神经磷酸酶，调控培养的乳鼠心室肌细胞离子通道重构。