Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling.
Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling.
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DOI：
10.3389/fcvm.2023.1074700
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发表时间：
2023
影响因子：
3.6
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
--
作者：
Theobald, Drew;Nair, Anand R.;Sriramula, Srinivas;Francis, Joseph
Toll样受体4（TLR 4）是启动先天性免疫应答的重要因子，在高血压和心肌梗死等心血管疾病中发挥重要作用。我们实验室以前的研究表明，阻断中枢TLR 4可以降低心脏TLR 4的表达，减轻高血压，改善心脏功能。然而，心脏特异性TLR 4在高血压和心脏重塑的发展中的作用尚不清楚。因此，我们假设心肌细胞特异性敲除TLR 4对高血压、心肌肥厚和重塑具有有益作用。为了检验这一假设，通过将floxed TLR 4小鼠与Myh 6-Cre小鼠杂交产生心肌细胞特异性TLR 4敲低（cTLR 4KO）小鼠，并使其经受血管紧张素II（Ang II，1 μg/kg/min或媒介物，持续14天）高血压模型。 使用无线电遥测的血压测量显示对照同窝小鼠和cTLR 4KO小鼠之间的基线平均动脉压没有差异（103 ± 2 vs. 105 ± 3 mmHg，p > 0.05）。 与对照小鼠相比，在cTLR 4KO小鼠中，Ang II诱导的高血压（132 ± 2对151 ± 3 mmHg，p < 0.01）减弱，心脏肥大（心脏/体重; 4.7对5.8 mg/g，p < 0.01）得到预防。 此外，心肌纤维化水平显著降低，心功能改善cTLR 4 KO小鼠输注Ang II。此外，心脏炎症，如左心室中TNF、IL-6和MCP-1的基因表达升高所证明的，在输注有Ang II的cTLR 4KO小鼠中减弱。总之，这些数据揭示了心肌细胞特异性TLR 4缺失通过抑制促炎细胞因子对Ang II诱导的高血压和心功能障碍的保护作用。
Toll-like receptor 4 (TLR4) is an integral factor in the initiation of the innate immune response and plays an important role in cardiovascular diseases such as hypertension and myocardial infarction. Previous studies from our lab demonstrated that central TLR4 blockade reduced cardiac TLR4 expression, attenuated hypertension, and improved cardiac function. However, the contribution of cardiac specific TLR4 to the development of hypertension and cardiac remodeling is unknown. Therefore, we hypothesized that cardiomyocyte specific knockdown of TLR4 would have beneficial effects on hypertension, cardiac hypertrophy, and remodeling. To test this hypothesis, cardiomyocyte-specific TLR4 knockdown (cTLR4KO) mice were generated by crossing floxed TLR4 mice with Myh6-Cre mice, and subjected to angiotensin II (Ang II, 1 µg/kg/min or vehicle for 14 days) hypertension model. Blood pressure measurements using radio telemetry revealed no differences in baseline mean arterial pressure between control littermates and cTLR4KO mice (103 ± 2 vs. 105 ± 3 mmHg, p > 0.05). Ang II-induced hypertension (132 ± 2 vs. 151 ± 3 mmHg, p < 0.01) was attenuated and cardiac hypertrophy (heart/body weight; 4.7 vs. 5.8 mg/g, p < 0.01) was prevented in cTLR4KO mice when compared with control mice. In addition, the level of myocardial fibrosis was significantly reduced, and the cardiac function was improved in cTLR4KO mice infused with Ang II. Furthermore, cardiac inflammation, as evidenced by elevated gene expression of TNF, IL-6, and MCP-1 in the left ventricle, was attenuated in cTLR4KO mice infused with Ang II. Together, this data revealed a protective role for cardiomyocyte-specific deletion of TLR4 against Ang II-induced hypertension and cardiac dysfunction through inhibition of proinflammatory cytokines.
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DOI：
10.1161/hypertensionaha.118.11065
发表时间：
2018-09
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Jia G;Aroor AR;Hill MA;Sowers JR
通讯作者：
Sowers JR
DOI：
10.1038/nrm3495
发表时间：
2013-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Muñoz-Durango N;Fuentes CA;Castillo AE;González-Gómez LM;Vecchiola A;Fardella CE;Kalergis AM
通讯作者：
Kalergis AM
影响因子：
10.8
作者：
Dange, Rahul B.;Agarwal, Deepmala;Francis, Joseph
通讯作者：
Francis, Joseph
影响因子：
9.3
作者：
Dange RB;Agarwal D;Teruyama R;Francis J
通讯作者：
Francis J