芪苈强心通过NRG-1/ErbB2通路减轻心脏微血管稀疏及改善射血分数保留心力衰竭的机制研究

Heart failure with preserved ejection fraction (HFpEF) is an important type of heart failure, while its pathological mechanisms remain largerly unknown and no evidence-based treatment is available. It is reported cardiac microvascular rarefaction was present in patients with HFpEF. Our previous study demonstrated that Qiliqiangxin (QL) could alleviate the extent of microvascular rarefaction and myocardial fibrosis in spontaneously hypertensive rats (SHR). We also found QL could up-regulate the expression of neuregulin-1 (NRG-1) and its membrane receptor ErbB2, alleviate cardiac microvascular rarefaction and improve cardiac systolic function in heart failure rats post myocardial infarction. Thus we hypothesize that QL could improve cardiac diastolic function and HFpEF by alleviating cardiac microvascular rarefaction (via promoting microangiogenesis, inhibiting endothelial-mesenchymal transition and decreasing endothelial cell loss) through NRG-1/ErbB2 dependent signaling pathways. In this study, on cellular level and with SHR induced HFpEF model, we aim to: 1) investigate the effects of QL on cardiac microvascular rarefaction and its relationship with diastolic dysfunction and HFpEF; 2) elucidate the intracellular signaling mechanisms of QL on NRG-1/ErbB2. This study will provide new insight and option for the prevention and treatment of HFpEF.

射血分数保留心力衰竭（HFpEF）是近年来备受重视的心力衰竭类型，发病机制不明，且无有效的治疗措施。有研究发现HFpEF患者存在心脏微血管稀疏现象。申请人前期研究发现芪苈强心方药（QL）具有减轻自发性高血压大鼠（SHR）心脏微血管稀疏和纤维化水平的作用，亦可上调NRG-1及膜受体ErbB2的表达、改善心梗后心衰大鼠心脏微血管稀疏及心脏收缩功能。故申请人设想QL通过上调NRG-1/ErbB2信号通路而减轻心脏微血管稀疏（促进微血管生成、抑制内皮间质化、减少内皮细胞丢失），进而改善心脏舒张功能不全和HFpEF。本课题拟在细胞模型和SHR致HFpEF大鼠模型，研究QL对心脏微血管稀疏和心脏舒张功能不全的作用，阐明QL调控NRG-1/ErbB2胞内信号减轻心脏微血管稀疏和改善心脏舒张功能不全的机制，为HFpEF防治提供新的实践探索和理论依据。

射血分数保留的心力衰竭(HFpEF)是近年来备受重视的心力衰竭类型，占心衰患者总数的 50%以上。目前除沙库巴曲缬沙坦外，尚无改善其预后的治疗药物。HFpEF 的病理生理机制复杂，目前认为多种病理因素损害心肌微血管内皮细胞(CMECs)导致心脏微血管稀疏引起心脏冠脉微循环功能障碍(CMD)，进而导致心脏舒张功能不全是HFpEF的重要病理生理机制。通过减少内皮细胞丢失、抑制内皮间质转化和促进血管生成等来减轻心脏微血管稀疏有望改善HFpEF心脏舒张功能、改善HFpEF患者的预后。传统中药芪苈强心方治疗心力衰竭具有多途径、多靶点的优势，但其对HFpEF心功能的保护作用及机制却鲜有报道。本研究在压力超负荷诱导的心脏舒张功能不全小鼠模型中发现芪苈强心方可以改善左室压力超负荷所致的小鼠心脏舒张功能不全、减轻心肌肥厚和心肌纤维化、改善心脏微血管稀疏；在AngII诱导的CMECs细胞模型中发现芪苈强心方通过上调ErbB2磷酸化水平，激活AKT-GSK3β信号轴，促进转录因子FoxO3a的磷酸化，使其胞质滞留，抑制FoxO3a核转移，进而抑制CMECs中AngII 过度激活的自噬，从而抑制AngII诱导的CMECs凋亡；还发现芪苈强心方能减轻高浓度AngII引起的CMECs增殖、迁移及血管新生损伤，芪苈强心方执行上述功能的分子机制是：上调Cxcr7的表达，进而激活AMPK-Nrf2信号轴，促进Nrf2的核转移。综上，本研究立足于传统通络方药芪苈强心方，以HFpEF心脏舒张功能不全为切入点，聚焦于HFpEF心脏微血管稀疏，阐明了芪苈强心方通过抑制CMECs凋亡和促进CMECs血管新生来改善心脏微血管稀疏，进而改善压力超负荷导致的小鼠心脏舒张功能不全的分子机制。为心脏舒张功能不全以及HFpEF的临床诊治提供了新的思路和证据。