Yan Jirong, Xi Zhichao, Guo Jiaying, Xu Lin, Sun Xueyang, Sha Wanjing, Liu Milin, Zhao Shenyu, Dai Enrui, Xu Yu, Xu Hongxi, Qu Huiyan
Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, No. 528, Zhangheng Road, Shanghai, 201203, China.
School of Pharmacy, Shanghai University of Traditional Chinese Medicine, No. 1200, Cailun Road, Shanghai, 201203, China.
Chin Med. 2023 Jul 28;18(1):90. doi: 10.1186/s13020-023-00803-y.
Ventricular remodeling is the adaptive process in which the heart undergoes changes due to stress, leading to heart failure (HF). The progressive decline in cardiac function is considered to contribute to intestinal barrier impairment. LuQi Formula (LQF) is a traditional Chinese medicine preparation widely used in the treatment of ventricular remodeling and HF. However, the role of LQF in the impairment of intestinal barrier function induced by ventricular remodeling remains unclear.
Ventricular remodeling was induced in rats by permanently ligating the left anterior descending branch coronary artery, and cardiac function indexes were assessed using echocardiography. Heart and colon tissue morphology were observed by hematoxylin-eosin, Masson's trichrome and Alcian Blue Periodic acid Schiff staining. Myocardial cell apoptosis was detected using TUNEL and immunohistochemistry. Circulatory levels of brain natriuretic peptide (BNP), intestinal permeability markers endotoxin, D-lactate and zonulin, as well as inflammatory cytokines tumor necrosis factor alpha and interleukin-1 beta were measured by Enzyme-linked immunosorbent assay. Expression levels of tight junction (TJ) proteins and hypoxia-inducible factor-1 alpha (HIF-1α) in colon tissue were detected by immunofluorescence, immunohistochemistry and western blotting. Cardiac function indexes and intestinal permeability markers of patients with HF were analyzed before and after 2-4 months of LQF treatment.
LQF protected cardiac function and alleviated myocardial fibrosis and apoptosis in rats with ventricular remodeling. LQF protected the intestinal barrier integrity in ventricular remodeling rats, including maintaining colonic tissue morphology, preserving the number of goblet cells and normal expression of TJ proteins. Furthermore, LQF upregulated the expression of HIF-1α protein in colon tissue. Intervention with a HIF-1α inhibitor weakened the protective effect of LQF on intestinal barrier integrity. Moreover, a reduction of HIF-1α aggravated ventricular remodeling, which could be alleviated by LQF. Correspondingly, the circulating levels of intestinal permeability markers and BNP in HF patients were significantly decreased, and cardiac function markedly improved following LQF treatment.
We demonstrated that LQF effectively protected cardiac function by preserving intestinal barrier integrity caused by ventricular remodeling, at least partially through upregulating HIF-1α expression.
心室重构是心脏因应激而发生变化的适应性过程，可导致心力衰竭（HF）。心脏功能的逐渐衰退被认为是肠道屏障受损的原因之一。潞芪方（LQF）是一种广泛用于治疗心室重构和HF的中药制剂。然而，LQF在心室重构所致肠道屏障功能损伤中的作用尚不清楚。
通过永久结扎大鼠左冠状动脉前降支诱导心室重构，采用超声心动图评估心脏功能指标。用苏木精-伊红染色、Masson三色染色和阿尔辛蓝过碘酸希夫染色观察心脏和结肠组织形态。采用TUNEL法和免疫组化法检测心肌细胞凋亡。采用酶联免疫吸附测定法检测脑钠肽（BNP）、肠道通透性标志物内毒素、D-乳酸和闭合蛋白的循环水平，以及炎性细胞因子肿瘤坏死因子α和白细胞介素-1β。通过免疫荧光、免疫组化和蛋白质印迹法检测结肠组织中紧密连接（TJ）蛋白和缺氧诱导因子-1α（HIF-1α）的表达水平。分析LQF治疗2-4个月前后HF患者的心脏功能指标和肠道通透性标志物。
LQF可保护心室重构大鼠的心脏功能，减轻心肌纤维化和细胞凋亡。LQF保护心室重构大鼠的肠道屏障完整性，包括维持结肠组织形态、保留杯状细胞数量和TJ蛋白的正常表达。此外，LQF上调结肠组织中HIF-1α蛋白的表达。用HIF-1α抑制剂干预可减弱LQF对肠道屏障完整性的保护作用。此外，HIF-1α的减少会加重心室重构，而LQF可缓解这一情况。相应地，HF患者肠道通透性标志物和BNP的循环水平显著降低，LQF治疗后心脏功能明显改善。
我们证明，LQF通过维持心室重构引起的肠道屏障完整性有效保护心脏功能，至少部分是通过上调HIF-1α的表达来实现的。
