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BackgroundPrevious studies have indicated elevated serum gastrin levels in individuals with HF. However, the association and underlying mechanisms between gastrin and HF remain unclear. This article aims to investigate the effects of gastrin on myocardial remodeling and HF, as well as its potential signal transduction mechanisms.MethodsIn vivo studies were initially conducted to investigate the relationship between gastrin and HF, as well as the effects of gastrin on myocardial remodeling and HF. Gastrin levels were measured using ELISA kits to assess their association with ISO-induced HF. Echocardio- graphy, qRT-PCR analysis of hypertrophy (ANP, BNP, β-MHC) and fibrosis markers (COL1, COL3, α-SMA), hematoxylin-eosin staining, and Masson’s trichrome staining were performed to evaluate the impact of gastrin on HF, MH, and fibrosis in mice.Furthermore, the effect of gastrin on cardiomyocyte hypertrophy was investigated in vitro using H9C2 cells, with F-actin staining and qRT-PCR analysis of ANP and BNP employed. Additionally, western blotting (WB) analysis of P-JAK2/JAK2, P-STAT3/STAT3, and P-ERK/ERK in cardiac tissues and cells was used to identify pathways through which gastrin modulates HF and myocardial remodeling.ResultsIn vivo study, the ISO-treated mice exhibited significantly increased gastrin levels compared to the control group (P ＜ 0.05). Furthermore, the ISO group showed significant cardiac hypertrophy, characterized by increased heart size, thickened ventricular walls, impaired cardiac function, and expanded fibrotic areas (P ＜ 0.05). In contrast, the gastrin-only group exhibited no significant pathological changes. Co-treatment with gastrin and ISO notably attenuated these pathological changes, whereas CI-988(a CCK2R inhibitor) admini- stration partially reversed gastrin’s protective effects (P ＜ 0.05). In vitro study,the ISO group exhibited a significantly larger cardiomyocyte surface area and elevated expression of hypertrophy-associated biomarkers (ANP and BNP) compared to controls (P ＜ 0.01). Gastrin treatment significantly suppressed these changes (P ＜ 0.01), but this protective effect was partly reversed by the CCK2R antagonist CI-988 (P ＜ 0.05). Additionally, phosphorylation levels of JAK2, STAT3, and ERK were significantly increased in the ISO group (P ＜ 0.05) both in mice cardiac tissues and H9C2 cells. Gastrin treatment suppressed these increases (P ConclusionsGastrin may exert protective effects against ISO-induced HF and myocardial remodeling by inhibiting the JAK2/STAT3 and ERK1/2 pathways via the CCK2 receptor.背景 既往研究显示，心力衰竭（Heart Failure，HF）患者的血清胃泌素水平升高，但胃泌素与心力衰竭之间的关联及其潜在机制仍未阐明。本研究旨在探讨胃泌素对心肌重构与心力衰竭的影响，以及其潜在的信号转导机制。 方法 本研究首先开展体内实验，以探讨胃泌素与心力衰竭的关联，以及胃泌素对心肌重构与心力衰竭的影响。采用酶联免疫吸附试验（enzyme-linked immunosorbent assay，ELISA）试剂盒检测血清胃泌素水平，以评估其与异丙肾上腺素（Isoproterenol，ISO）诱导的心力衰竭的相关性。通过超声心动图、实时定量聚合酶链反应（quantitative real-time polymerase chain reaction，qRT-PCR）分析肥厚标志物[心房钠尿肽（Atrial Natriuretic Peptide，ANP）、B型钠尿肽（B-type Natriuretic Peptide，BNP）、β-肌球蛋白重链（β-myosin heavy chain，β-MHC）]及纤维化标志物[I型胶原（Collagen type I，COL1）、III型胶原（Collagen type III，COL3）、α-平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）]的表达，同时采用苏木精-伊红染色与马松三色染色，评估胃泌素对小鼠心力衰竭、心肌肥厚（Myocardial Hypertrophy，MH）及纤维化的影响。此外，本研究采用H9C2细胞开展体外实验，探究胃泌素对心肌细胞肥厚的影响，通过F-肌动蛋白染色及qRT-PCR分析ANP与BNP的表达水平进行验证。另外，通过对心脏组织与细胞中的磷酸化JAK2/总JAK2（P-JAK2/JAK2）、磷酸化STAT3/总STAT3（P-STAT3/STAT3）及磷酸化ERK/总ERK（P-ERK/ERK）进行蛋白质印迹法（Western Blotting，WB）分析，明确胃泌素调控心力衰竭与心肌重构的信号通路。 结果 体内实验结果显示，与对照组相比，异丙肾上腺素干预的小鼠血清胃泌素水平显著升高（P < 0.05）。此外，异丙肾上腺素组小鼠出现显著的心肌肥厚，表现为心脏体积增大、心室壁增厚、心功能受损及纤维化区域扩大（P < 0.05）。与之相比，单纯胃泌素干预组未出现显著的病理改变。联合使用胃泌素与异丙肾上腺素可显著减轻上述病理改变，而给予胆囊收缩素2受体（Cholecystokinin 2 Receptor，CCK2R）抑制剂CI-988可部分逆转胃泌素的保护作用（P < 0.05）。体外实验结果显示，与对照组相比，异丙肾上腺素组小鼠的心肌细胞表面积显著增大，肥厚相关生物标志物ANP与BNP的表达水平显著升高（P < 0.01）。胃泌素干预可显著抑制上述变化（P < 0.01），但该保护作用可被CCK2R拮抗剂CI-988部分逆转（P < 0.05）。此外，异丙肾上腺素组小鼠的心脏组织及H9C2细胞中，JAK2、STAT3及ERK的磷酸化水平均显著升高（P < 0.05），胃泌素干预可抑制这些磷酸化水平的升高。 结论 胃泌素可能通过胆囊收缩素2受体（CCK2R）抑制JAK2/STAT3与ERK1/2信号通路，从而发挥对抗异丙肾上腺素诱导的心力衰竭及心肌重构的保护作用。