H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose.
H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose.
复制标题
H3 松弛素通过高糖条件下心脏成纤维细胞中 ROS 和 P2X7R 介导的 NLRP3 炎性体激活来抑制胶原蛋白合成
DOI：
10.1111/jcmm.13464
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发表时间：
2018-03
影响因子：
5.3
通讯作者：
Yin X
中科院分区：
文献类型：
--
作者：
Zhang X;Fu Y;Li H;Shen L;Chang Q;Pan L;Hong S;Yin X
高糖诱导的活性氧簇（ROS）的过度产生和P2 X7 R激活增加了NLRP 3炎性体的激活，从而导致糖尿病心肌病的发病机制。虽然H3松弛素已被证明可以抑制异丙肾上腺素诱导的心脏纤维化，但其机制尚未得到很好的研究。在这里，我们证明了高糖（HG）通过激活NLRP 3炎性体诱导胶原合成，导致新生大鼠心脏成纤维细胞中caspase-1激活，白细胞介素-1 β（IL-1β）和IL-18分泌。此外，我们使用新生大鼠心脏成纤维细胞的高糖模型，并表明ROS和P2 X7 R的活化增强，ROS和P2 X7 R介导的NLRP 3炎性小体活化对胶原合成至关重要。ROS和P2 X7 R的抑制降低了NLRP 3炎性体介导的胶原蛋白合成，与H3松弛素的作用相似。此外，H3松弛素通过ROS-和P2 X7 R-介导的NLRP 3炎性小体激活减少胶原合成。这些结果提供了H3松弛素通过在HG条件下抑制ROS和P2 X7 R来抑制NLRP 3炎性体介导的胶原合成的机制，并表明H3松弛素代表了缓解糖尿病心肌病心脏纤维化的潜在药物。
Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.
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