Abstract 18876: Cardiomyocyte-Specific Deletion of TLR4 Attenuates Angiotensin II-Induced Hypertension and Improves Cardiac Function
Toll-like receptor 4 (TLR4) plays an important role in inflammatory cardiovascular diseases including hypertension. We have previously showed that central TLR4 inhibition delayed progression of hypertension and improved cardiac function. However, the involvement of cardiac specific TLR4 in hypertension has not been fully explored. Therefore, in this study we investigated the role of cardiomyocyte specific knockdown of TLR4 on hypertension, cardiac hypertrophy and remodeling. Mice with cardiomyocyte-specific deletion of TLR4 (cTLR4-/-) were generated by crossing floxed TLR4 mice with Myh6-Cre mice. Twelve-week old cTLR4-/- mice and littermates were infused with angiotensin II (Ang II, 1μg/kg/min) or vehicle (s.c. osmotic pumps, 2 weeks). Baseline blood pressure was not different between control littermates and cTLR4-/- mice (telemetry; 106.7 ±5 vs 107.2 ±4 mmHg, n=5, p>0.05). Ang II-induced hypertension (128 ±3 vs. 149 ±3 mmHg, n=5, p<0.01) was attenuated and cardiac hypertrophy (heart/body weight; 4.8 vs 5.9 mg/g, n=5, p<0.01) was prevented in cTLR-/- mice when compared with control mice. In addition, cTLR4-/- mice exhibited a reduced hypertrophic phenotype upon Ang II treatment. The cardiac hypertrophy markers ANP (2-fold, p<0.05 vs vehicle) and TGF-β (3-fold, p<0.01 vs vehicle) were significantly attenuated in cTLR4-/- mice with Ang II treatment. Concomitantly, the level of myocardial fibrosis was significantly reduced and the cardiac function as measured with echocardiography (LVPWd: 0.49 ±0.03 vs 0.59 ±0.02; FS%: 29.6 ±0.9 vs 22.7 ±0.8; p<0.01 vs control+Ang II) was also significantly ameliorated in cTLR4-/- mice upon Ang II-treatment. In addition, Ang II-infusion increased inflammation (qRT-PCR), as shown by elevated gene expression of TNF, IL-6 and MCP-1 (9-, 8-, and 6-fold, respectively, p<0.01 vs. vehicle) in the left ventricle, which was attenuated in cTLR4-/- mice (2-, 1.2-, and 2.5-fold respectively, p<0.01 vs control+Ang II). In summary, our data shows that cardiac-specific deletion of TLR4 attenuates the development of hypertension and cardiac remodeling, and improves cardiac function. These results demonstrate that cardiac TLR4 plays an important role in the blood pressure control, cardiac hypertrophy, and inflammation.
- Inflammation and inflammatory markers
- Cardiac hypertrophy
- Molecular biology
- Blood pressure
Author Disclosures: S. Sriramula: None. Y. Saini: None. R. Dharmakumar: None. J. Francis: None.
- © 2016 by American Heart Association, Inc.