β1-肾上腺素能信号通路介导的炎症小体致心力衰竭作用及机制研究

Heart failure (HF) has been one of the refractory cardiovascular diseases threatening human health, whereas its pathogenesis is still uncertain, which may be associated with inflammasome and beta 1- adrenergic signal pathway. It has been reported that the development of HF is always accompanied with activation of beta-adrenergic signal pathway, and inflammasome induced during myocardial infarct could promote apoptosis and fibrosis of myocardial cells. Our previous experiments found that myocardial cell beta 1-adrenergic signal pathway was hyperactive, myocardial cell autophagy was inhibited and inflammasome was activated. Based on the present knowledge and our preliminary experiment results, we put forward the following hypothesis, i.e., activation of beta 1-adrenergic signaling pathway can activate inflammasome of myocardial cells, which induces apoptosis and fibrosis of myocardial cells, and resulting in the occurrence of HF. To test this hypothesis, the mechanisms of beta 1-adrenergic signal pathway on activation of inflammasome during HF will be investigated from molecule, cell, tissue and animal levels by using HF animal model, molecular biology, patch clamp and calcium imaging experiments to provide experimental and theoretical basis targeting inflammasome for new strategies of HF therapy.

心力衰竭（HF）已成为严重威胁人类健康的难治疾病之一，但其发病机制尚不完全清楚，可能与肾上腺素能信号通路和炎症小体有关。研究表明，HF时常伴有肾上腺素能信号通路的激活。申请者前期实验研究发现，在HF大鼠的心肌细胞中β1-肾上腺素能信号通路活性增加，心肌细胞自噬水平降低，炎症小体过度活化。因此，根据既往研究报道和申请者前期实验研究结果提出如下假说：β1-肾上腺素能信号通路激活可诱导心肌细胞炎症小体的产生，导致心肌细胞凋亡、心肌纤维化和心室重构，从而引起HF的发生。为验证这一假说，申请者拟通过建立HF动物模型，采用分子生物学、膜片钳和钙离子成像等实验技术，从分子、细胞、组织和动物整体水平探讨β1-肾上腺素能信号通路介导的炎症小体致HF作用和机制，研究结果可能为HF患者的治疗提供新途径。

心力衰竭（HF）是各种器质性心脏病的终末期表现，以心脏扩大、心肌纤维化为特征，已成为严重威胁人类健康的难治疾病之一，但其发病机制尚不完全清楚。本研究通过主动脉缩窄法建立大鼠心肌肥厚/心力衰竭模型，发现心衰大鼠肾上腺素能信号通路过度活化，炎症小体激活。通过去甲肾上腺素刺激体外培养心肌细胞，实验发现心肌细胞炎症小体被激活，而阻断β肾上腺素能信号通路、L型钙通道和活性氧后去甲肾上腺素激活炎症小体受到抑制。进一步实验发现去甲肾上腺素能促进心肌纤维化，阻断炎症小体后心肌纤维化减少。此外，给予大鼠口服β受体阻滞剂能抑制心肌炎症小体活化及心肌纤维化，从而抑制心衰的发生发展。本研究结果表明β肾上腺素能信号通路可通过激活炎症小体从而促进心肌纤维化，导致心力衰竭的发生、发展。因此，调控β肾上腺素能信号通路/L 型钙通道/活性氧/炎症小体通路可能为治疗心力衰竭提供新的靶点。