Bacillus Calmette-Guerin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment
Bacillus Calmette-Guerin and TLR4 agonist prevent cardiovascular hypertrophy and fibrosis by regulating immune microenvironment
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卡介苗和TLR4激动剂通过调节免疫微环境预防心血管肥厚和纤维化
DOI：
10.4049/jimmunol.180.11.7349
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Hu, Zhuo-Wei
中科院分区：
文献类型：
--
作者：
Liu, Yu-Ying;Cai, Wen-Feng;Hu, Zhuo-Wei
高血压引起的心血管肥大和纤维化在心力衰竭的发展中至关重要。TLRs的活性参与了压力超负荷引起的心肌肥厚和心肌纤维化的发展。我们想知道是否疫苗卡介苗（BCG），激活TLR 4引发免疫反应，调节压力超负荷刺激的心血管肥大和心脏纤维化的小鼠模型腹主动脉缩窄（AAC）诱导的高血压。在AAC之前或之后，动物接受BCG、TLR 4激动剂、IFN-γ或TLR 4拮抗剂i. p. BCG和TLR 4激动剂显著预防AAC诱导的心血管肥大和反应性心脏纤维化，而血流动力学没有变化。此外，TLR 4拮抗剂逆转BCG和TLR 4激动剂诱导的抗心血管肥大和心脏纤维化的作用。BCG可降低心肌组织中TLR 2和TLR 4的表达，而TLR 4激动剂可增加浸润心肌组织的免疫细胞中TLR 2和TLR 4的表达。这导致心脏中IFN-γ/TGF-β的表达比率增加。BCG和TLR 4激动剂的心脏保护作用与其调节心脏内ERK-Akt和p38-NF-κ B信号通路有关。总之，TLR 4的活性在压力超负荷诱导的心肌肥厚和纤维化的介导中起着关键作用。BCG和TLR 4激动剂对免疫应答的调节在防治高血压心肌肥厚和心肌纤维化方面具有巨大的潜力。
Hypertension-induced cardiovascular hypertrophy and fibrosis are critical in the development of heart failure. The activity of TLRs has been found to be involved in the development of pressure overload-induced myocardial hypertrophy and cardiac fibrosis. We wondered whether vaccine bacillus Calmette-Guerin (BCG), which activated TLR4 to elicit immune responses, modulated the pressure overload-stimulated cardiovascular hypertrophy and cardiac fibrosis in the murine models of abdominal aortic constriction (AAC)-induced hypertension. Before or after AAC, animals received BCG, TLR4 agonist, IFN-gamma, or TLR4 antagonist i.p. BCG and TLR4 agonist significantly prevented AAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist reversed the BCG- and TLR4 agonist-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. BCG decreased the expression of TLR2 or TLR4 on the heart tissue but TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells that infiltrate into the heart tissue. This led to an increased expression ratio of IFN-gamma/TGF-beta in the heart. The cardiac protective effects of BCG and TLR4 agonist are related to their regulation of ERK-Akt and p38-NF-kappa B signal pathways in the heart. In conclusion, the activity of TLR4 plays a critical role in the mediation of pressure overload-induced myocardial hypertrophy and fibrosis. The regulation of immune responses by BCG and TLR4 agonist has a great potential for the prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.