Dexmedetomidine Promotes Lipopolysaccharide-Induced Differentiation of Cardiac Fibroblasts and Collagen I/III Synthesis through α(2A) Adrenoreceptor-Mediated Activation of the PKC-p38-Smad2/3 Signaling Pathway in Mice.
Dexmedetomidine Promotes Lipopolysaccharide-Induced Differentiation of Cardiac Fibroblasts and Collagen I/III Synthesis through α(2A) Adrenoreceptor-Mediated Activation of the PKC-p38-Smad2/3 Signaling Pathway in Mice.
复制标题
右美托咪定通过 α2A 肾上腺素受体介导的 PKC-p38-Smad2/3 信号通路激活促进脂多糖诱导的心脏成纤维细胞分化和胶原蛋白 I/III 合成
DOI：
10.3390/ijms222312749
复制
发表时间：
2021-11-25
影响因子：
5.6
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Liao J;Li K;Su X;Chen Y;Wang Y;Tang X;Xing Y;Xu Y;Dai X;Teng J;Li H;Wang H;Lv X;Wang Y
右美托咪定（DEX）是一种选择性α2肾上腺素能受体（AR）激动剂，常用于危重病期间的镇静药物。本研究探讨了DEX对LPS介导的心肌成纤维细胞（CF）分化的促进作用及其可能机制。LPS可明显增加小鼠CFs中α-SMA和I/III型胶原的表达及p38和Smad-3的磷酸化水平。DEX通过增加LPS刺激后CFs α2A-AR的表达而增强上述作用。α2A-AR基因敲除小鼠的CFs对DEX治疗的敏感性明显低于野生型小鼠。蛋白激酶C（PKC）的抑制取消DEX对LPS诱导的CFs分化的增强作用。第二代CFs中α-SMA的表达明显高于未传代和第一代CFs。LPS刺激后，未传代的CFs释放的TNF-α明显高于第1代和第2代CFs。DEX对LPS诱导的CFs释放TNF-α和IL-6无影响。进一步的研究表明，DEX促进小鼠暴露于LPS四周的心脏纤维化和胶原I/III的合成。结果表明，DEX通过激活α2A-AR，通过PKC-p38-Smad 2/3信号通路有效促进LPS诱导的CFs向肌成纤维细胞分化。
Dexmedetomidine (DEX), a selective α2 adrenergic receptor (AR) agonist, is commonly used as a sedative drug during critical illness. In the present study, we explored a novel accelerative effect of DEX on cardiac fibroblast (CF) differentiation mediated by LPS and clarified its potential mechanism. LPS apparently increased the expression of α-SMA and collagen I/III and the phosphorylation of p38 and Smad-3 in the CFs of mice. These effects were significantly enhanced by DEX through increasing α2A-AR expression in CFs after LPS stimulation. The CFs from α2A-AR knockout mice were markedly less sensitive to DEX treatment than those of wild-type mice. Inhibition of protein kinase C (PKC) abolished the enhanced effects of DEX on LPS-induced differentiation of CFs. We also found that the α-SMA level in the second-passage CFs was much higher than that in the nonpassage and first-passage CFs. However, after LPS stimulation, the TNF-α released from the nonpassage CFs was much higher than that in the first- and second-passage CFs. DEX had no effect on LPS-induced release of TNF-α and IL-6 from CFs. Further investigation indicated that DEX promoted cardiac fibrosis and collagen I/III synthesis in mice exposed to LPS for four weeks. Our results demonstrated that DEX effectively accelerated LPS-induced differentiation of CFs to myofibroblasts through the PKC-p38-Smad2/3 signaling pathway by activating α2A-AR.
登录
查看更多内容
影响因子：
10.8
作者：
MEDUGORAC, I;JACOB, R
通讯作者：
JACOB, R
影响因子：
5.6
作者：
Huang, Libing;Zhu, Juan;Zhu, Minghui
通讯作者：
Zhu, Minghui
影响因子：
8
作者：
Kong, Ping;Christia, Panagiota;Frangogiannis, Nikolaos G.
通讯作者：
Frangogiannis, Nikolaos G.
DOI：
10.1016/s0022-2828(03)00210-4
发表时间：
2003-10-01
影响因子：
5
作者：
Sato, H;Watanabe, A;Yokoyama, T
通讯作者：
Yokoyama, T
影响因子：
20.1
作者：
Miragoli, Michele;Salvarani, Nicolo;Rohr, Stephan
通讯作者：
Rohr, Stephan