医学分子生物学杂志 ›› 2024, Vol. 21 ›› Issue (3): 203-210.doi: 10.3870/j.issn.1672-8009.2024.03.003

• 论著 • 上一篇    下一篇

全反式维甲酸减轻内质网应激反应改善异丙肾上腺素诱导的大鼠心肌纤维化与心肌重构 #br#

  

  1. 海南医学院第一附属医院1心血管内一科,2心电图室 海口市, 570102
  • 出版日期:2024-05-31 发布日期:2024-06-14
  • 基金资助:
    海南省卫生健康行业科研项目 (No. 22A200077), 海南省自然科学基金青年项目 ( No. 821QN401), 海南医学院第一附属医院青年培育基金 (No. HYYFYPY202020)

All-trans Retinoic Acid Alleviates Endoplasmic Reticulum Stress and Improves Isoproterenol Induced Myocardial Fibrosis and Myocardial Remodeling in Rats #br#

  1. 1 Department of Cardiology,2ECG Room, First Affiliated Hospital of Hainan Medical College, Haikou, 570102, China
  • Online:2024-05-31 Published:2024-06-14

摘要: 目的 全反式维甲酸 (all-trans retinoic acid, ATRA) 对异丙肾上腺素 ( isoprenaline, ISO) 诱导下大鼠心肌纤维化和心肌重构的影响及作用机制方法 将大鼠按随机数表法分为 4 : 对照组、 ISO 、ATRA + ISO 、 4-PBA (4-苯基丁酸, 4-phenylbutyric acid) + ISO , 每组 10 ; ATRA + ISO 组和 4-PBA + ISO 组预先分别通过腹腔注射 ATRA 4-PBA, 然后再通过背部皮下注射 ISO 进行诱导心脏超声检测各组大鼠左心室舒张末期内径 (left ventricular internal diameter in diastole, LVIDd)、 左心室收缩末期内径 ( left ventricular internal diameter in systole, LVIDs)、 左心室的射血分数 ( ejection fraction, EF) 及短轴缩短率(fractional shortening, FS), 称量各组大鼠体重全心质量及左心室质量, 计算全心质量指数 ( heart mass index, HMI) 与左心室质量指数 (left ventricle mass index, LVMI)。 ELISA 测定各组大鼠血清 N B 型利钠肽原 (N terminal pro B type natriuretic peptide, NT-proBNP) 含量。 HE 染色和 Masson 染色观察各组大鼠心肌组织病理学变化与胶原纤维化程度蛋白质印迹检测心肌组织中 G 蛋白偶联受体 78 ( glucose-regulated protein 78, GRP78)、 C / EBP 同源蛋白 (C / EBP homology protein, CHOP)、 蛋白激酶 R 样内质网激酶 ( protein kinase R-like ER kinase, PERK)、 磷酸化真核翻译起始因子 2α (phosphorylated eukaryotic translation initiation factor 2α, p-eIF2α)、 转化生长因子-β1 ( transforming growth factor-β1, TGF-β1)、 α-平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)、 胶原蛋白 Collagen-Ⅰ Collagen-Ⅲ 的蛋白表达结果 与对照组比较, ISO 组大鼠 EF FS 显著降低 ( P< 0. 05), LVIDd、 LVIDs、 HMI LVMI 显著升高 ( P< 0. 05), 血清 NTproBNP 含量显著增加 (P< 0. 05), 心肌组织病理损伤明显, 胶原纤维面积显著增加 ( P< 0. 05), 心肌组织中 GRP78、 CHOP、 PERK、 p-eIF2α、 TGF-β1、 α-SMA、 Collagen-Ⅰ Collagen-Ⅲ 蛋白表达均显著上调 ( P< 0. 05); ISO 组比较, ATRA + ISO 组和 4-PBA + ISO 组的大鼠 EF FS 显著升高 ( P < 0. 05), LVIDd、LVIDs、 HMI LVMI 显著降低 (P< 0. 05), 血清 NT-proBNP 含量显著减少 (P< 0. 05), 心肌组织损伤程度明显减轻, 胶原纤维面积显著减小 (P< 0. 05), 心肌组织中 GRP78、 CHOP、 PERK、 p-eIF2α、 TGF-β1、 α- SMA、 Collagen-Ⅰ Collagen-Ⅲ 蛋白表达均显著下调 (P< 0. 05)。 结论 ATRA 能够减轻 ISO 诱导的大鼠心肌损伤及其纤维化, 抑制心肌重构, 改善心功能, 该作用与其抑制内质网应激反应有关

关键词: 心肌重构, 心肌纤维化, 异丙肾上腺素, 全反式维甲酸, 内质网应激

Abstract: Objective To investigate the effects of all-trans retinoic acid (ATRA) on myocardial fibrosis and myocardial remodeling induced by isoproterenol (ISO) in rats, and to analyze itsmechanism. Methods The rats were randomly divided into 4 groups: control group, ISO group,ATRA + ISO group, 4-phenylbutyric acid (4-PBA) + ISO group, with 10 rats in each group. Rats in the ATRA + ISO group and the 4-PBA + ISO group were administrated with ATRA and 4-PBA through intraperitoneal injection respectively. Rats in the ISO group, the ATRA + ISO group and the 4-PBA + ISO group were administrated with ISO through subcutaneous injection on the back. The left ventricular internal diameter in diastole ( LVIDd), left ventricular internal diameter in systole ( LVIDs), left ventricular ejection fraction (EF) and fractional shortening (FS) were detected by cardiac ultrasound. The body weight, whole heart mass and left ventricular mass of rats were weighed, and the whole heart mass index ( HMI) and left ventricular mass index ( LVMI) were calculated. The level of serum N-terminal pro B type natriuretic peptide ( NT-proBNP) was determined by ELISA. HE staining and Masson staining were used to observe the histopathological changes and the degree of collagen fibrosis in rat myocardial tissues, respectively. The protein expression levels of G protein-coupled receptor 78 (GRP78), C / EBP homologous protein (CHOP), protein kinase R-like endoplasmic reticulum kinase (PERK), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), and transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA), Collagen-I and Collagen-Ⅲ in myocardial tissues were determined by Western blotting. Results When compared with those in the control group, the EF and FS in the ISO group were significantly decreased (P < 0. 05), the LVIDd, LVIDs, HMI and LVMI were significantly increased (P< 0. 05), the level of serum NT-proBNP was significantly increased (P< 0. 05), thepathological injury of myocardial tissues was observed, the areas with collagen fiber had significantlyincreased (P< 0. 05), the protein expression levels of GRP78, CHOP, PERK, P-EIF2α, TGF-β1, α-SMA, Collagen Ⅰ and Collagen Ⅲ in the myocardial tissues were significantly up-regulated(P< 0. 05). When compared with those in the ISO group, the EF and FS in the ATRA + ISO group and the 4-PBA + ISO group were significantly increased ( P < 0. 05), the LVIDd, LVIDs, HMI and LVMI were significantly decreased (P< 0. 05), and the level of serum NT-proBNP was significantly decreased (P< 0. 05), the degree of myocardial injury was significantly reduced, the area with collagen fiber had significantly reduced ( P < 0. 05 ), and the protein expression levels ofGRP78, CHOP, PERK, P-EIF2α, TGF-β1, α-SMA, Collagen Ⅰ and Collagen Ⅲ in the myocardial tissue were significantly down-regulated (P< 0. 05). Conclusion ATRA can alleviate ISOinduced myocardial injury and fibrosis, inhibit myocardial remodeling and improve cardiac function through the inhibition of endoplasmic reticulum stress response.

Key words:

myocardial remodeling, myocardial fibrosis, isoproterenol, all-trans retinoicacid, endoplasmic reticulum stress

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