目的 探讨隐丹参酮通过调控酪氨酸蛋白激酶/信号转导和转录激活因子3（JAK2/STAT3）信号通路减轻异丙肾上腺素（ISO）诱导的大鼠心肌纤维化（MF）的作用及机制。方法 将60只SD雄性大鼠随机分为对照组、模型组、卡托普利（6.75 mg·kg^-1，阳性对照）组和隐丹参酮低、高剂量（40、80 mg·kg^-1）组，每组12只。除对照组外，每天固定时间给予大鼠背部sc ISO 5 mg·kg^-1，连续10 d，建立MF模型。各组大鼠每天于ISO注射前1 h ig给药，持续4周，对照组和模型组则用等量蒸馏水代替药物。超声心动仪评估大鼠的心功能，包括左室舒张末期内径（LVIDd）、左室收缩末期内径（LVIDs）、左室射血分数（LVEF）和缩短分数（LVFS）；检测心脏指数、心胫比；试剂盒法检测血清肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL^-1β）和白细胞介素-6（IL-6）水平，心肌组织中超氧化物歧化酶（SOD）和丙二醛（MDA）含量；苏木精-伊红（HE）和Masson染色观察心肌组织炎症及纤维化，计算胶原容积分数（CVF）；免疫组化检测胶原蛋白Ⅰ和Ⅲ（Col Ⅰ和ColⅢ）表达； Western blotting法检测基质金属蛋白酶-9（MMP-9）、组织金属蛋白酶抑制剂1（TIMP-1）、信号转导与转录激活因子3（STAT3）、p-STAT3、JAK2、p-JAK2蛋白表达。结果 与对照组相比，模型组大鼠明显出现心功能减退，心脏指数和心胫比增高；心肌细胞增大、排列紊乱，间质内有大量成纤维细胞、炎细胞浸润； Masson染色显示CVF升高；血清TNF-α、IL^-1β和IL-6水平升高；心肌组织中SOD含量降低、MDA含量升高，Col Ⅰ和Col Ⅲ阳性表达增多，MMP-9表达增加和TIMP-1表达减少； p-JAK2和p-STAT3表达增加，差异均有统计学意义（P＜0.001）。与模型组相比，隐丹参酮组大鼠心功能障碍明显改善，心脏指数和心胫比显著降低，心肌细胞形态和分布相对正常，CVF显著降低，血清TNF-α、IL^-1β和IL-6水平显著降低，心肌组织中MDA含量显著减少、SOD含量显著升高，Col Ⅰ和Col Ⅲ阳性表达减少，MMP-9蛋白表达显著降低，TIMP-1蛋白表达显著增加，p-JAK2和p-STAT3蛋白表达显著降低，差异均有统计学意义（P＜0.05、0.01、0.001）。结论 隐丹参酮通过抑制JAK2/STAT3通路激活，调控炎症-氧化应激级联反应，减少胶原沉积，从而改善ISO诱导的MF。

Objective To explore the effect and mechanism of cryptotanshinone on alleviating isoproterenol (ISO)-induced myocardial fibrosis (MF) in rats through regulating the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Methods Sixty male SD rats were randomly divided into the control group, the model group, the captopril (6.75 mg·kg^-1,positive control) group, and the cryptotanshinone low-dose (40 mg·kg^-1) and high-dose (80 mg·kg^-1) groups, with 12 rats in each group. Except for the control group, ISO 5 mg·kg^-1 was subcutaneously injected into the back of rats at a fixed time every day for 10 consecutive days to establish the MF model. Rats in each group were intragastrically administered drugs 1 h before ISO injection every day for four weeks, while the control group and the model group were given the same volume of distilled water instead of drugs. Echocardiography was used to evaluate the cardiac function of rats, including left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS). The heart coefficient and heart-tibia ratio were measured. The levels of serum tumor necrosis factor-α (TNF-α), interleukin-1β (IL^-1β), and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay (ELISA). The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in myocardial tissue were measured by colorimetric assay. HE and Masson staining were used to observe myocardial inflammation and fibrosis, and the collagen volume fraction (CVF) was calculated. The expressions of collagen type I and III (Col I and Col III) were detected by immunohistochemistry. The expressions of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), STAT3, p-STAT3, JAK2, and p-JAK2 proteins were detected by Western blotting. Results Compared with the control group, the model group showed significant cardiac dysfunction, increased heart coefficient and heart-tibia ratio; enlarged myocardial cells with disordered arrangement, and a large number of fibroblasts and inflammatory cells infiltrating in the interstitium; Masson staining showed CVF increased; Levels of serum TNF-α, IL^-1β, and IL-6 elevated; SOD content decreased and MDA content increased in myocardial tissue; Positive expressions of Col I and Col III increased; MMP-9 expression increased and TIMP-1 expression decreased; Expressions of p-JAK2 and p-STAT3 increased, all with statistically significant differences (P < 0.001). Compared with the model group, the cryptotanshinone groups showed significant improvement in cardiac dysfunction, significantly decreased heart coefficient and heart-tibia ratio, relatively normal myocardial cell morphology and distribution, significantly decreased CVF, significantly decreased levels of serum TNF-α, IL^-1β, and IL-6, significantly decreased MDA content and significantly increased SOD content in myocardial tissue, decreased positive expressions of Col I and Col III, significantly decreased MMP-9 protein expression, significantly increased TIMP-1 protein expression, and significantly decreased expressions of p-JAK2 and p-STAT3, all with statistically significant differences (P < 0.05, 0.01, 0.001). Conclusion Cryptotanshinone alleviates ISO-induced MF by inhibiting JAK2/STAT3 pathway activation, modulating the inflammation-oxidative stress cascade, and reducing collagen deposition.

R285.5

齐齐哈尔医学科学院项目（QMSI2021B-13）；国家级大学生创新创业训练计划项目（202211230054）；齐齐哈尔医学院研究生创新基金项目（QYYCX2024-30）