H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation
H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation
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DOI：
10.1159/000481843
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发表时间：
2017-10
影响因子：
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通讯作者：
Xiaohui Zhang;L. Pan;Kelaier Yang;Yu Fu;Yue Liu;Jinyu Chi;Xin Zhang;Siting Hong;Xiao Ma-
中科院分区：
文献类型：
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作者：
Xiaohui Zhang;L. Pan;Kelaier Yang;Yu Fu;Yue Liu;Jinyu Chi;Xin Zhang;Siting Hong;Xiao Ma-
背景/目的：细胞凋亡、纤维化和NLRP 3炎性小体激活参与糖尿病心肌病（DCM）的发生发展。人重组松弛素-3（H3 relaxin-3，H3 relaxin）是一种新的抑制心肌损伤的生物活性肽，但H3 relaxin是否能预防DCM大鼠的心肌损伤及其机制尚不清楚。研究方法：为了研究H3松弛素对DCM的作用，我们在链脲佐菌素（STZ）诱导的糖尿病（DM）雄性SD大鼠中进行了使用H3松弛素治疗的研究。在大鼠注射STZ（65 mg/kg）后4周和8周，我们通过蛋白质印迹分析测量了大鼠心脏中的细胞凋亡、纤维化和NLRP 3炎性体标记物。随后，在STZ治疗后2或6周，大鼠用H3松弛素[2 μg/kg/d（A组）或0.2 μg/kg/d（B组）]治疗2周。采用超声心动图评价糖尿病大鼠的心功能，以确定心肌损伤的程度。采用心肌细胞凋亡、纤维化和NLRP 3炎性小体标记物的蛋白水平来评估心肌损伤。此外，我们使用Milliplex MAP大鼠细胞因子/趋化因子磁珠试剂盒测定了IL-1β和IL-18的血浆水平。结果如下：与对照组相比，STZ诱导的糖尿病心脏中切割的caspase-8、caspase-9和caspase-3以及纤维化标志物的蛋白表达在4周和8周时增加。此外，NLRP 3炎性体在STZ诱导的糖尿病心脏中基本上被激活，导致IL-1β和IL-18水平增加。与DM组相比，A组表现出明显更好的心功能。H3松弛素可抑制糖尿病大鼠心肌细胞凋亡。H3松弛素抑制纤维化标志物的蛋白表达。此外，H3松弛素也有效地减弱了NLRP 3炎性体的蛋白表达和活化。结论：本研究首次证实H3松弛素在DCM中具有抗凋亡、抗纤维化和抗炎作用。
Background/Aims: Apoptosis, fibrosis and NLRP3 inflammasome activation are involved in the development of diabetic cardiomyopathy (DCM). Human recombinant relaxin-3 (H3 relaxin) is a novel bioactive peptide that inhibits cardiac injury; however, whether H3 relaxin prevents cardiac injury in rats with DCM and the underlying mechanisms are unknown. Methods: To investigate the effect of H3 relaxin on DCM, we performed a study using H3 relaxin treatment in male Sprague-Dawley (SD) rats with streptozotocin (STZ)-induced diabetes (DM). We measured apoptosis, fibrosis and NLRP3 inflammasome markers in the rat hearts four and eight weeks after the rats were injected with STZ (65 mg/kg) by western blot analysis. Subsequently, 2 or 6 weeks after the STZ treatment, the rats were treated with H3 relaxin [2 µg/kg/d (A group) or 0.2 µg/kg/d (B group)] for 2 weeks. Cardiac function was evaluated by echocardiography to determine the extent of myocardial injury in the DM rats. The protein levels of apoptosis, fibrosis and NLRP3 inflammasome markers were used to assess myocardial injury. In addition, we determined the plasma levels of IL-1β and IL-18 using a Milliplex MAP Rat Cytokine/Chemokine Magnetic Bead Panel kit. Results: The protein expression of cleaved caspase-8, caspase-9 and caspase-3 as well as fibrosis markers increased at 4 and 8 weeks in the STZ-induced diabetic hearts compared with the levels in the control group. Furthermore, the NLRP3 inflammasome was substantially activated in STZ-induced diabetic hearts, leading to increased IL-1β and IL-18 levels. Compared with the DM group, the A group exhibited substantially better cardiac function. The protein levels of apoptosis markers were attenuated by H3 relaxin, indicating that H3 relaxin inhibited myocardial apoptosis in the hearts of diabetic rats. The protein expression of fibrosis markers was inhibited by H3 relaxin. Additionally, the protein expression and activation of the NLRP3 inflammasome were also effectively attenuated by H3 relaxin. Conclusions: This study is the first to demonstrate that H3 relaxin plays an anti-apoptotic, anti-fibrotic and anti-inflammatory role in DCM.