Protective effect of low dose gadolinium chloride against isoproterenol-induced myocardial injury in rat
Protective effect of low dose gadolinium chloride against isoproterenol-induced myocardial injury in rat
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小剂量氯化钆对异丙肾上腺素所致大鼠心肌损伤的保护作用
DOI：
10.1007/s10495-015-1147-8
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发表时间：
2015
期刊：
影响因子：
7.2
通讯作者：
Luo Da-Li
中科院分区：
文献类型：
--
作者：
Zheng Yuan-Yuan;Zhang Hai-Hong;Yan Xin-Xin;Chen Min;Qi Tian-Yu;Zhang Lan-E;Luo Da-Li
急性心肌损伤是世界范围内发病率和死亡率最高的原因之一，大量花生四烯酸（AA）的释放与心肌细胞凋亡和坏死有关。以前的研究表明GdCl_3完全阻断AA诱导的Ca ~（2+）反应。本研究旨在探讨氯化钆（GdCl 3）对异丙肾上腺素（ISO）诱导的心肌损伤的保护作用及其机制。将大鼠随机分为5组：对照组、GdCl 3组、ISO组、ISO + GdCl 3组和ISO +维拉帕米组。ELISA法检测血清AA水平，TTC染色检测心肌梗死面积，TUNEL法检测心肌细胞凋亡。通过质谱和紫外光谱法研究了AA和GdCl 3之间的化学相互作用。用Western blot法检测心肌细胞死亡受体相关分子的表达及向脂筏的转位。与ISO组相比，GdCl 3组心肌损伤明显减轻，心肌肌钙蛋白I、乳酸脱氢酶、肌酸激酶MB和AA恢复至正常水平，梗死面积减少，细胞凋亡减少。此外，AA-Fas通路的激活被发现在ISO诱导的心肌损伤，这是取消GdCl 3。此外，AA诱导细胞凋亡，通过聚集和激活死亡受体相关分子TNFR 1，Fas和FADD的脂筏，一个过程中显着阻止预处理与GdCl 3。GdCl 3与AA的摩尔比为1/3时，AA的化学结构发生了明显的变化，GdCl 3对AA诱导的Ca ~（2+）反应和细胞凋亡的抑制作用最强。总之，本研究首次证明，GdCl 3保护心肌对ISO诱导的细胞凋亡，通过，至少部分地，作为AA的清除剂，因此取消其下游激活的死亡受体调节的凋亡途径。
Acute myocardial injury remains a leading cause of morbidity and mortality worldwide, and large amount of released arachidonic acid (AA) is found to be related to cardiomyocyte apoptosis and necrosis. Previous study suggested that GdCl3completely abolished AA-induced Ca2+response. Thus, this study aims to investigate possible cardioprotection effect of GdCl3on isoproterenol (ISO)-induced myocardial injury and its underlying mechanism(s). Rats that were randomly allocated to five groups: control, GdCl3, ISO, ISO + GdCl3, and ISO + verapamil. Serum levels of AA and cardiac markers, infarct area, and cell apoptosis in heart were measured by ELISA assay, TTC and TUNEL staining, respectively. Chemical interaction between AA and GdCl3was evaluated by mass and UV spectrometry. The expressions and translocations of death receptor related molecules into lipid rafts were detected in neonatal rat ventricular myocytes by Western blots. Compared with ISO-administered rats, GdCl3significantly ameliorated the myocardium injury, demonstrated by restoring serum cardiac troponin I, lactate dehydrogenase, creatine kinase MB and AA to near normal levels, and decreasing infarct area and cell apoptosis. In addition, an activation of AA-Fas pathway was found in ISO-induced myocardial injury, which was abrogated by GdCl3. Furthermore, AA induced cell apoptosis through clustering and activating death receptor related molecules TNFR1, Fas and FADD in lipid rafts, a process significantly prevented by the pretreatment with GdCl3. Finally, GdCl3at the molar ratio of 1/3 (GdCl3/AA) was mostly effective in abolishing AA-induced Ca2+response and cell apoptosis, because an obvious change in the chemical identity of AA was obtained by GdCl3according to this molar ratio. In conclusion, this study demonstrates for the first time that GdCl3protects myocardium against ISO-induced cell apoptosis through, at least partly, serving as a scavenger of AA, therefore abolishing its downstream activation of the death receptor regulated apoptosis pathway.