粒细胞集落刺激因子通过 JAK2-STAT3 通路减轻兔冠状动脉微栓塞模型的心肌重构和室性心律失常易感性。
Granulocyte colony-stimulating factor attenuates myocardial remodeling and ventricular arrhythmia susceptibility via the JAK2-STAT3 pathway in a rabbit model of coronary microembolization.
机构信息
Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
Department of Cardiology, Fujian Provincial People's Hospital, Fuzhou, 350004, China.
出版信息
BMC Cardiovasc Disord. 2020 Feb 17;20(1):85. doi: 10.1186/s12872-020-01385-5.
BACKGROUND
Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME.
METHODS
Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively.
RESULTS
Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P < 0.01), indicating less severe myocardial damage and arrhythmias. The G-CSF group showed higher phosphorylated-Cx43 expression (P < 0.01 vs. CME). Those G-CSF-induced changes were reversed by A490, indicating the involvement of JAK2. G-CSFR, phosphorylated-JAK2, and phosphorylated-STAT3 protein levels were higher in the G-CSF group than in the AG490 (P < 0.01) and Sham (P < 0.05) groups.
CONCLUSION
G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.
背景
冠状动脉微栓塞（CME）预后不良，其中室性心律失常是最严重的后果。了解其潜在机制可能有助于改善其管理。本研究旨在探讨粒细胞集落刺激因子（G-CSF）对 CME 后连接蛋白 43（Cx43）表达和室性心律失常易感性的影响。
方法
40 只雄性家兔随机分为 4 组（每组 10 只）：假手术组（Sham）、CME 组、G-CSF 组和 AG490（JAK2 选择性抑制剂）组。CME 组、G-CSF 组和 AG490 组通过左前降支（LAD）动脉导管插入术和 CME 造模。G-CSF 组和 AG490 组分别给予腹腔注射 G-CSF 和 G-CSF+AG490。通过超声心动图评估心室结构，通过心脏电生理学分析心室电生理特性，通过 Masson 和苏木精-伊红染色分别评估心肌间质胶原含量和形态特征。
结果
采用 Western blot 和免疫组化分析 Cx43、G-CSF 受体（G-CSFR）、JAK2 和 STAT3 的表达。与 CME 组相比，G-CSF 组心室有效不应期（VERP）、VERP 离散度、室性心动过速/颤动的诱发性和致死性降低（P<0.01），表明心肌损伤和心律失常较轻。G-CSF 组磷酸化 Cx43 表达升高（P<0.01 比 CME 组）。AG490 逆转了 G-CSF 诱导的这些变化，表明 JAK2 参与其中。G-CSF 组 G-CSFR、磷酸化 JAK2 和磷酸化 STAT3 蛋白水平高于 AG490 组（P<0.01）和 Sham 组（P<0.05）。
结论
G-CSF 可能通过 JAK2-STAT3 信号转导减轻心肌重构，从而降低 CME 后室性心律失常的易感性。
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