目的 探討隱丹參酮通過調(diào)控酪氨酸蛋白激酶/信號轉(zhuǎn)導(dǎo)和轉(zhuǎn)錄激活因子3（JAK2/STAT3）信號通路減輕異丙腎上腺素（ISO）誘導(dǎo)的大鼠心肌纖維化（MF）的作用及機制。方法 將60只SD雄性大鼠隨機分為對照組、模型組、卡托普利（6.75 mg·kg^-1，陽性對照）組和隱丹參酮低、高劑量（40、80 mg·kg^-1）組，每組12只。除對照組外，每天固定時間給予大鼠背部sc ISO 5 mg·kg^-1，連續(xù)10 d，建立MF模型。各組大鼠每天于ISO注射前1 h ig給藥，持續(xù)4周，對照組和模型組則用等量蒸餾水代替藥物。超聲心動儀評估大鼠的心功能，包括左室舒張末期內(nèi)徑（LVIDd）、左室收縮末期內(nèi)徑（LVIDs）、左室射血分數(shù)（LVEF）和縮短分數(shù)（LVFS）；檢測心臟指數(shù)、心脛比；試劑盒法檢測血清腫瘤壞死因子-α（TNF-α）、白細胞介素-1β（IL^-1β）和白細胞介素-6（IL-6）水平，心肌組織中超氧化物歧化酶（SOD）和丙二醛（MDA）含量；蘇木精-伊紅（HE）和Masson染色觀察心肌組織炎癥及纖維化，計算膠原容積分數(shù)（CVF）；免疫組化檢測膠原蛋白Ⅰ和Ⅲ（Col Ⅰ和ColⅢ）表達； Western blotting法檢測基質(zhì)金屬蛋白酶-9（MMP-9）、組織金屬蛋白酶抑制劑1（TIMP-1）、信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3（STAT3）、p-STAT3、JAK2、p-JAK2蛋白表達。結(jié)果 與對照組相比，模型組大鼠明顯出現(xiàn)心功能減退，心臟指數(shù)和心脛比增高；心肌細胞增大、排列紊亂，間質(zhì)內(nèi)有大量成纖維細胞、炎細胞浸潤； Masson染色顯示CVF升高；血清TNF-α、IL^-1β和IL-6水平升高；心肌組織中SOD含量降低、MDA含量升高，Col Ⅰ和Col Ⅲ陽性表達增多，MMP-9表達增加和TIMP-1表達減少； p-JAK2和p-STAT3表達增加，差異均有統(tǒng)計學(xué)意義（P＜0.001）。與模型組相比，隱丹參酮組大鼠心功能障礙明顯改善，心臟指數(shù)和心脛比顯著降低，心肌細胞形態(tài)和分布相對正常，CVF顯著降低，血清TNF-α、IL^-1β和IL-6水平顯著降低，心肌組織中MDA含量顯著減少、SOD含量顯著升高，Col Ⅰ和Col Ⅲ陽性表達減少，MMP-9蛋白表達顯著降低，TIMP-1蛋白表達顯著增加，p-JAK2和p-STAT3蛋白表達顯著降低，差異均有統(tǒng)計學(xué)意義（P＜0.05、0.01、0.001）。結(jié)論 隱丹參酮通過抑制JAK2/STAT3通路激活，調(diào)控炎癥-氧化應(yīng)激級聯(lián)反應(yīng)，減少膠原沉積，從而改善ISO誘導(dǎo)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

齊齊哈爾醫(yī)學(xué)科學(xué)院項目（QMSI2021B-13）；國家級大學(xué)生創(chuàng)新創(chuàng)業(yè)訓(xùn)練計劃項目（202211230054）；齊齊哈爾醫(yī)學(xué)院研究生創(chuàng)新基金項目（QYYCX2024-30）