Theobald Drew, Nair Anand R, Sriramula Srinivas, Francis Joseph
Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, NC, United States.
Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United States.
Front Cardiovasc Med. 2023 Mar 24;10:1074700. doi: 10.3389/fcvm.2023.1074700. eCollection 2023.
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, > 0.05). Ang II-induced hypertension (132 ± 2 vs. 151 ± 3 mmHg, < 0.01) was attenuated and cardiac hypertrophy (heart/body weight; 4.7 vs. 5.8 mg/g, < 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.
Toll样受体4（TLR4）是先天免疫反应启动中的一个不可或缺的因素，在高血压和心肌梗死等心血管疾病中发挥着重要作用。我们实验室之前的研究表明，中枢性TLR4阻断可降低心脏TLR4表达，减轻高血压，并改善心脏功能。然而，心脏特异性TLR4对高血压发展和心脏重塑的作用尚不清楚。因此，我们假设心肌细胞特异性敲低TLR4对高血压、心脏肥大和重塑具有有益作用。为了验证这一假设，通过将携带floxed TLR4的小鼠与Myh6-Cre小鼠杂交，构建了心肌细胞特异性TLR4敲低（cTLR4KO）小鼠，并将其用于血管紧张素II（Ang II，1 μg/kg/min或溶媒，持续14天）高血压模型。使用无线电遥测技术测量血压发现，对照同窝小鼠和cTLR4KO小鼠的基线平均动脉压没有差异（103±2 vs. 105±3 mmHg，>0.05）。与对照小鼠相比，cTLR4KO小鼠中Ang II诱导的高血压（132±2 vs. 151±3 mmHg，<0.01）得到减轻，心脏肥大（心脏/体重；4.7 vs. 5.8 mg/g，<0.01）得到预防。此外，在输注Ang II的cTLR4KO小鼠中，心肌纤维化水平显著降低，心脏功能得到改善。此外，在输注Ang II的cTLR4KO小鼠中，左心室中TNF、IL-6和MCP-1基因表达升高所证明的心脏炎症也得到减轻。总之，这些数据揭示了心肌细胞特异性缺失TLR4通过抑制促炎细胞因子对Ang II诱导的高血压和心脏功能障碍具有保护作用。
